Book Oasis
Book Oasis
Book Oasis
Introduction
In 1963, the late Dr. Ernesto Contreras, Sr. opened the Oasis
of Hope Hospital and initiated what would become a healing tradition
known as the Total Care Approach. Dr. Contreras is recognized in
multiple publications as a pioneer in body, mind, and spirit medicine.
At the foundation of his philosophy were two principles inspired
by Hippocrates, the father of medicine, and Jesus Christ, The Great
Physician: 1) First, do no harm; 2) Love your patient as you love
yourself.
Because of his philosophy, Dr. Contreras taught his medical
staff to never prescribe treatments that would destroy the quality of
life of the patient. He also insisted that Oasis of Hope physicians
offer therapies that they would be willing to take if in the same
circumstances. His emphasis on the doctor-patient relationship,
along with his integration of natural and conventional therapies with
emotional and spiritual counseling, were the principle reasons why
more than 100,000 patients from 55 nations have come to Oasis of
Hope for treatment over the last 45 years.
Dr. Contreras believed that to be effective as a physician,
one had to blend art and science. When treating cancer patients,
Dr. Contreras looked beyond the obvious. He would find the root
needs of his patients and develop personalized therapies to address
the unique circumstance of each. His commitment to treat his
patients with professionalism, ethics, and compassion made him a
beloved doctor. As a researcher, Dr. Contreras explored hundreds of
treatment modalities in his constant quest to help his patients. His
untiring determination inspired his staff and patients alike.
At age 88, after 62 years of medical practice, Dr. Contreras
went on to be with the Lord. Two of his significant contributions
to humanity were his model for intregrative medicine and the
Preface
My people perish for lack of knowledge, wrote the
prophet Hosea. How true this is in the arena of cancer. For that
reason, continual education of ourselves, of our patients, and
of society at large is a paramount commitment of the Oasis of
Hope Health Group. Finding practical ways to avoid and control
the scourge of cancer is the chief focus of these efforts.
As is well known, the risk for developing specific types
of cancer by a given age is quite often a function of modifiable
lifestyle factors. More and more, epidemiology suggests that one
can greatly lower the risk for certain cancers by measures such
as: 1) Adopting a quasi-vegan diet low in fatty animal products.
This diet includes an ample intake of fruits and cruciferous
vegetables such as cabbage, broccoli, and cauliflower. It also
includes vegetables rich in alliums such as garlic and onions; 2)
Maintaining leanness and good insulin sensitivity with regular
exercise and smart eating habits; 3) Achieving good vitamin D
status and optimal selenium nutrition; 4) Avoiding overt mutagens
such as tobacco smoke or excessive sun exposure.
Nonetheless, the probability of developing some lifethreatening form of cancer is significant, even if every feasible
effort is taken to lower ones risk. Thats not true for a number
of the other dangerous disorders that afflict Western society. At
least until recently, coronary heart disease and diabetes have been
virtually unheard of in many cultures where the traditional diets
are low in fatty animal products and an active lifestyle helps to
keep people lean. Stroke, and even Alzheimers disease, seem to
be quite rare wherever people have eaten an unsalted diet most
their lives.
Conversely, thanks largely to clean water, sanitation,
and vaccination programs, people in the First World now enjoy
substantial protection from infectious disorders such as smallpox,
cholera, typhus, the plague, and tuberculosis that wiped out
tens of millions of people in past centuries. But cancer has
been an uncontrolled threat for centuries, and continues to be.
The inevitability of cancer as one ages, reflects the fact that
mutations gradually accumulate in body cells that have replicative
potential (stem cells) and sooner or later, these mutations will
give rise to colonies of rogue cells that evade normal growth
control mechanisms, and eventually gain the ability to spread
unchecked throughout the body. Unfortunately, cancer is an
equal opportunity offender that respects no gender, age or social
status.
Hoping for the cure is not recommended. Thats
because cancer isnt just one disease its a family of hundreds of
diseases. Within each histological type of cancer, each persons
individual case of cancer is distinct the cells in one persons
breast cancer are bio-chemically distinct from another persons
breast cancer. Since cancer cells usually continue to accumulate
new mutations at an accelerated rate, the characteristics of cancer
cells within a single case of cancer in a single person may vary
markedly, depending on location. This rapid mutability also
means that cancers are good at evolving resistance to whatever
therapeutic measures are thrown at them.
Of course, many cancers are curable by surgery or
radiotherapy if caught at a sufficiently early stage. But,
unfortunately, cancers are often caught too late for this satisfying
outcome to be feasible. For most adult cancers, once stage 4 is
reached, the cancer is generally considered to be incurable.
But incurable is not the same as untreatable or
uncontrollable. Thanks largely to the rapidly evolving science
of molecular biology, cancer scientists are gaining much greater
Table of Contents
1
Cancer is a Tough Opponent
Cancer can be and often is a very wily opponent. In large
measure, this reflects the fact that it is a constantly moving target.
To understand why cancers can be so elusive, one must start with
how cancers arise.
2
Oasis of Hope Integrative Regulatory Therapies:
A Multi-Focal Strategy for Cancer Control
Cancer is heavy-handed. There is nothing subtle at all
about the presence of a malignant tumor in the kidney or lung.
Cancer makes no attempt to veil its threat. It is a disease that can
gather momentum quickly and attack with frightening ferocity.
Only a concerted and combined effort can repel such an attack.
Dr. Contreras, Sr. believed that to defeat cancer, it was necessary
to attack it from every possible angle. He understood the
importance of both direct and indirect approaches. The foundation
of the Metabolic Therapy that he devised is its multi-faceted
approach. Yes, we do attack the tumor, but we also stimulate the
immune system, shield normal healthy tissues from the attack,
and address causal factors. The total care approach requires the
patients full participation. Cancer treatment is not a spectator
sport. The patient must be prepared for the fight. We go through
a process of structuring a patient for success by providing the
necessary resources to face the threat at the physical, emotional,
and spiritual levels. There is no question that the alliance between
body, mind, and spirit can even the playing field against cancer.
In the chapters that follow, the Oasis of Hope body/mind/spirit
medicine therapeutic protocols will be explained. The present
chapter constitutes an overview that will explain how Oasis of
Hope attacks cancer, sensitizes it to this attack, cuts off its supply
lines, and block its avenues of spread.
It is probably unrealistic to expect that the wonder
drug for curing cancer is just about to emerge from some
What sets Oasis of Hope apart from many other clinics
employing chemotherapy is its use of many adjuvant measures
intended to make the chemotherapy more effective at annihilating
cancer cells, while simultaneously minimizing the damage done to
healthy tissues. These measures are cited very briefly here. Later
in the book, a more detailed explanation of these measures, with
citations of the relevant biomedical literature, will be provided.
Oasis of Hope has also developed a novel strategy for
increasing the chemosensitivity of cancer cells that nevertheless
remain hypoxic. Recent research demonstrates that hypoxia
protects tumor cells, at least in part, by diminishing the capacity
of these cells to produce an intracellular signaling factor known
as cyclic GMP (cGMP). Prior to chemotherapy, Oasis of Hope
administers high oral doses of the B-vitamin biotin. In high
concentrations, biotin has been shown to directly stimulate cGMP
production, both in tumors and healthy tissues. Fortunately,
increased cGMP doesnt seem to influence the chemosensitivity
of cells that are well oxygenated, so biotin shouldnt boost the
chemosensitivity of healthy tissues.
Chemosensitizing Agents
Recent rodent research shows that high but tolerable
intakes of the antioxidant nutrient selenium can boost the
chemosensitivity of many types of cancer while making healthy
tissues more chemoresistant. With this rationale, Oasis of Hope
employs high-dose selenium supplementation prior to and during
chemotherapy. Another agent, which boosts the chemosensitivity
of many cancers is the activated metabolite of vitamin D
(calcitriol). Since some cancers are capable of making their own
calcitriol when supplied with vitamin D, we use high but safe
doses of that vitamin in conjunction with chemotherapy.
In many cancers, their relative chemoresistance reflects
increased intracellular activity of a factor known as NF-kappaB.
Since the natural drug salicylate and the herbal compound
silibinin have shown the capacity to inhibit NF-kappaB activity
in clinically feasible doses, these agents are also employed as
chemosensitizing agents in the IRT-Q protocols.
Quite commonly, patients comment on how much better
they tolerated chemotherapy at Oasis of Hope compared with
prior negative experiences with chemotherapy at other clinics.
This, despite the fact that Oasis of Hope physicians dont hold
back when it comes to dosing. The increase in efficacy, coupled
with the decrease in negative side effects, reflects thoughtful
planning.
3
Oasis of Hope At - Home Therapies
With most chemotherapies, it is necessary to give the
body at least a few weeks to heal before another course of
chemotherapy is administered. This is why Oasis of Hope patients
go home for several weeks in between courses of chemotherapy.
Oasis of Hope provides its patients with an elaborate at-home
therapeutic regimen with the intent of slowing the grow-back of
remaining tumors between sessions of chemotherapy. The rate
of tumor grow-back between cycles of chemotherapy can have
an important impact on the chances for a curative outcome, or
at least for significant tumor control. If the tumor grows back
so rapidly that the number of malignant cells eliminated by a
course of chemotherapy is entirely replaced by the growing
tumor before another round of therapy can be administered, the
at-home strategy will at best temporarily keep the tumor in check.
On the other hand, chemotherapy may have a chance to induce a
substantial remission if each course kills a significant number of
cells, and grow-back between chemo sessions is slow.
Patients in the IRT-C protocol also return home for several
weeks between their courses of ascorbate infusions. They receive
the same At-Home therapeutic regimen as patients receiving
IRT-Q. The rationale of the At-Home therapy in IRT-C is the
same to slow the grow-back of tumor between sessions of inhospital vitamin C infusions.
The therapeutic strategies described here are also
employed in the long-term follow-up (or maintenance) therapy
prescribed for Oasis of Hope patients after they have completed
an IRT-Q or IRT-C protocol.
Suppressing Angiogenesis
A key strategy that Oasis of Hope uses to impede the
angiogenic process is called metronomic chemotherapy. This
entails the daily use of one or more chemotherapy drugs in a dose
so low that no significant toxicity to healthy tissues or side effects
result. Remarkably, such chemotherapy has been shown to be
selectively toxic to endothelial cells that are engaged in building
new blood vessels for the tumor. There is reason to believe that
the anti-diabetes drug pioglitazone, included in the At-Home
regimens, will further boost the sensitivity of endothelial cells to
metronomic chemotherapy.
Other nutraceuticals and drugs employed in the At-Home
regimens with potential for slowing angiogenesis include: The
chief compound in green tea polyphenols (EGCG), the amino acid
glycine, salsalate, silibinin, diclofenac, valproic acid, vitamin D,
and fish oil.
Preventing Metastases
The At-Home regimens include one agent that specifically
targets the metastatic process modified citrus pectin derived
from the chief form of fiber in citrus fruits. This absorbable form
of pectin interacts with galectin-3, a type of molecular hook that
cancer cells, when circulating in the bloodstream, use to attach
themselves to the walls of small blood vessels (capillaries). This
sort of attachment is required before a cancer cells can migrate
through the capillary wall to establish a new metastasis. Modified
citrus pectin suppresses this process by blocking the grasping
function of galectin-3.
Preventing Cachexia
A substantial loss of muscle mass (cachexia) is a common
complication of advanced cancer. Although loss of appetite
associated with decreased calorie consumption is typically
seen with this syndrome, the substantial loss of muscle mass
associated with cachexia reflects an inflammatory reaction in
skeletal muscle fibers that is much more severe than that loss of
muscle mass seen with caloric restriction alone. In some patients,
this loss of muscle mass becomes so severe that it contributes to
death by severely weakening the respiratory muscles. The Oasis
of Hope At-Home regimen includes several elements that have
potential for preventing cachexia, including salsalate, melatonin,
glutamate, and fish oil.
Oasis of Hope was one of the first cancer clinics to include
music, laughter, and art therapies as options for its patients.
Alteration of Lifestyle
While patients receive treatment at Oasis of Hope, we begin to
educate them on how to live healthy lives when they return home
and how to continue therapy. Oasis of Hope doctors and nurses
work with patients and their loved ones to teach them how to
effectively self-administer therapies. This is a very cost-effective
way for patients to continue therapy for a prolonged period of
time.
Doctors at Oasis of Hope Hospital have observed that
the patients who get the best results are those who make a real
4
The Oasis of Hope Difference
The therapy regimens offered by Oasis of Hope are
distinguished by the fact that they are:
Personalized Although the IRT-Q and IRT-C regimens
are rather well defined, they are personalized in line with the
particular needs of each patient. The choice of chemotherapy
drug employed will depend upon the type of cancer, the stage
of its spread, and the physical condition of the patient. The
adjuvant regimen can be modified as needed to insure that that it
is well tolerated by the patient, and that it is the most appropriate
regimen for the tumor type. Patients who prefer to avoid cytotoxic
chemotherapy drugs can be treated with the IRT-C protocol. Oasis
of Hope doctors do their best to inform patients of the potential
benefits and risks associated with the therapeutic protocols which
they recommend and it is ultimately the patient who decides
whether a recommended protocol is implemented.
Integral and Integrative As should be clear from the
foregoing discussion, no effort is spared to maximize both the
efficacy and the tolerability of therapy regimens. The focus
is on a diverse array of targets and the utilization of a wide
range of available nutraceuticals and safe drugs. This is done
within the context of a program that strives to optimize the
psychological and overall physical status of the patient, with the
Dynamic The medical scientists who devise the IRT-Q and IRT-C
regimens are constantly scanning the latest credible biomedical
literature to enhance their understanding of cancer and to improve
the efficacy and scope of the Oasis of Hope therapy regimens.
That means that these regimens are in a constant state of revision
and new agents, or improved forms or dosages of agents already
in use, are frequently incorporated into them. Oasis of Hope
strives to define the cutting edge of integrative cancer treatment.
5
Oxidizing Cancer to Death
Oxidant Stress and How Cells Cope with It
It is common knowledge that free radicals and
oxidants are important mediators of disease but what are
these compounds? In most stable molecules, electrons occur
in pairs. Molecules that contain unpaired electrons tend to be
unstable and are known as radicals or free radicals. Because
they are unstable, they have a tendency to extract another electron
from another molecule, or to donate their unpaired electron to
another molecule. In either case, the attacked molecule is usually
converted to a radical in the process. In living cells, this can give
rise to a chain reaction of molecular damage.
The chief way in which free radicals arise in a bodys cells
is by donation of an electron to molecular oxygen, generating a
compound known as superoxide. This reaction can be catalyzed
by several natural enzymatic reactions in cells. Superoxide
can then, via spontaneous or enzyme-catalyzed reactions, give
rise to other reactive compounds such as hydrogen peroxide or
peroxynitrite. These compounds are not themselves free radicals,
but they often give rise to free radicals, and they also can act to
alter the structure and function of proteins by oxidizing them.
Unsaturated fatty acids in membranes are also prone to oxidation
by free radicals.
Because unabated damage by free radicals and oxidants
can cause major and often adverse changes in the structures
of cellular proteins and fats, living organisms have developed
antioxidant mechanisms.
Certain enzymes, as well as electron-donor molecules
known as antioxidants, can fix free radicals by electron
donation.
This can work in other ways to prevent or undo the
damage to biological molecules wrought by oxidant reactions.
Examples include enzymes such as superoxide dismutase,
catalase, glutathione peroxidase, and thioreductase, and
antioxidant molecules such as glutathione and vitamins C and E.
In normal healthy cellular metabolism, the production of oxidants
is balanced by the action of antioxidant mechanisms that prevent
free radical damage from getting out of hand and overwhelming
the cell. But sometimes, either because of excess production
of radicals and oxidants, or because of inadequately protective
antioxidant mechanisms, free radical damage can get the upper
hand a condition known as oxidant stress. Oxidant stress is
not always bad. In fact, induction of oxidant stress is one way in
which some cytotoxic drugs kill cancer cells. On the other hand,
as we shall see, a constant moderate level of oxidant stress in
some cancers renders them more aggressive and harder to kill.
Ahigh proportion of cancers have low activity of the enzyme
catalase, which degrades the oxidant chemical hydrogen peroxide1-3.
This adaptation may be beneficial to the cancer. Although oxidant
chemicals can be toxic to cells, moderate increases in oxidant
stress aid the growth and survival of many cancers4-7. However,
low catalase makes cancers potentially vulnerable to attack with
hydrogen peroxide. Recently, researchers at the National Institutes
of Health have discovered that high concentrations of vitamin
C (ascorbate) can react spontaneously with molecular oxygen
within tumors to generate large amounts of hydrogen peroxide,
which can be lethal to tumor cells whose catalase activity is low8,9.
Vitamin K3 as an Adjuvant
The ability of ascorbate (vitamin C) to generate hydrogen
peroxide in tumors apparently hinges on the presence of unknown
catalysts that can transfer electrons from ascorbate to oxygen
molecules, generating the unstable compound superoxide8,9. The
latter is rapidly converted to hydrogen peroxide, which can move
into cancer cells, and mediates the tumor cell death achieved with
successful ascorbate therapy. Dr. Mark Levine, whose research
encouraged us to develop the IRT-C protocol, speculates that
extracellular protein-bound iron serves as this catalyst9. It is
conceivable that the availability of this catalyst might vary from
tissue to tissue and person to person, depending on nutritional
status or genetics. Furthermore, there is no reason to assume that
levels of this catalyst are sufficient to permit an optimally intense
generation of hydrogen peroxide in tissues.
However, it is not necessary to rely on unknown
endogenous catalysts for this purpose. Certain small soluble
organic molecules can perform the same catalytic function,
expediting the transfer of electrons from ascorbate to oxygen.
In particular, menadione, also known as vitamin K3, has this
capacity14. Menadione may be particularly appropriate for
They also demonstrate that ascorbate/menadione can
interact synergistically with certain cytotoxic chemotherapy
drugs in killing cancer cells, presumably because a concurrent
increase in oxidant stress can make these drugs more lethal 24. This
observation has been independently confirmed25. Indeed, there are
reports that menadione alone can potentiate the cytotoxicity of
certain chemotherapy agents, presumably because, in sufficiently
high concentrations, intracellular menadione can generate oxidant
stress by transferring electrons from intracellular molecules to
oxygen26,27. Injectible vitamin K3 is administered, just prior to the
vitamin C infusions, with the hope and expectation that inclusion
of menadione in the ascorbate infusions will markedly potentiate
generation of hydrogen peroxide in tumors, enabling a more
substantial cell kill in those cancers that are sufficiently low in
catalase activity.
The net result is more oxygen delivery to the tumor 29,30. Many
tumors contain regions in which oxygen content is low, and
hypoxic tumor cells typically are harder to kill with radiotherapy
or chemotherapy. Thus, protocols which can boost tumor oxygen
levels have potential as adjuvant measures in cancer therapy.
Recently, researchers at the Canary Islands Institute for Cancer
Research recruited 18 cancer patients and used special needle
probes to measure the oxygen content of their tumors before and
after 3 sessions of O3-AHT. They were in fact able to establish
that there were fewer hypoxic tumor regions following O3-AHT 29
At Oasis of Hope, O3-AHT is used not only in conjunction
with chemotherapy, but also with high-dose intravenous sodium
ascorbate therapy for IRT-C. This strategy involves drawing 200
ml of a patients blood, treating it with a mixture of ozone and
oxygen, and re-infusing it.
This procedure is typically repeated several times weekly.
It is important to stress that Oasis of Hope employs an O3-AHT
protocol that has been widely utilized in Europe for decades with
an excellent safety record. The safety of this strategy reflects
the fact that no ozone is infused into the body. Ozone is very
unstable, and for practical purposes is completely dissipated
before the ozone-treated blood is returned to the body. Thus,
the body is exposed to ozone oxidation products, rather than
ozone itself. Exposure of blood to ozone in clinically appropriate
amounts does not cause lysis of red blood cells, or compromise
the functional viability of white cells. No evident side effects are
noted in patients receiving O3-AHT.
Oasis of Hope also has a novel perfluorochemical emulsion
known as Perftec that is an oxygen carrier. When infused into
a patient, it greatly boosts the total oxygen carrying capacity of
blood31. After Perftec infusion, patients are asked to breathe air
that is enriched in oxygen content, so that the circulating Perftec
is loaded with optimal amounts of oxygen.
The combination of ozone autohemotherapy and Perftec
infusion can be expected to improve oxygen availability in
hypoxic regions of tumors. This in turn should boost the ability
of intravenous ascorbate and vitamin K to generate hydrogen
peroxide in tumors.
Concurrent Chemotherapy
Many patients will also receive cancer chemotherapy on
the same day that they receive intravenous vitamin C. There are
reasons to believe that the oxidant stress induced by the vitamin
C in the tumor, as well as the improved tumor oxygenation made
possible by ozone therapy and Perftec, will often increase the ability
of the administered chemotherapy drugs to kill cancer cells 32-38.
The Oasis of Hope Vitamin C Protocol has been designed to
exploit these complementary interactions so that destruction of
cancer cells can be maximized without increasing the toxic risk
to healthy tissues.
Although many patients will be treated with chemotherapy,
some will not. In some cases, the type of cancer is known to be
resistant to available chemotherapy drugs. In other cases, patients
elect to forego chemotherapy for personal reasons. For these
patients, it is hoped that a vitamin C & K3/tumor oxygenation
regimen will be sufficient to achieve worthwhile destruction of
the tumor.
chemotherapy and hydrogen peroxide by inhibiting the activity
of NF-kappaB 39,40. This factor is activated in a high proportion
of advanced cancers, and works in multiple ways to render these
cancers less sensitive to chemotherapy and oxidant stress 41,42.
Although the drug aspirin is a chemical relative of salicylate,
the latter does not have the potential to cause bleeding ulcers or
43,44
. The main common side effect
kidney failure as aspirin does
of salicylic acid therapy is a reversible impairment of ear function
associated with a mild loss of hearing acuity and/or ringing in
the ears (tinnitus). These problems go away after salicylate is
discontinued 45. At Oasis of Hope Hospital, the form of salicylate
we use is known as salsalate (Disalcid). This is less likely to
46
cause stomach upset than is sodium salicylate .
Prior to receiving vitamin K3 and vitamin C (and possibly
chemotherapy), patients are also supplemented with the nutrient
selenium and the herb silymarin, which is a source of the natural
anti-inflammatory compound silibinin.
Like salicylate, these agents have potential for sensitizing
tumors to destruction by chemotherapy or oxidant stress.
Silymarins activity in this regard may be similar to salicylates.
47,48
. Recent studies show
It suppresses activation of NF-kappaB
that high doses of organic selenium can make cancer cells more
sensitive to many types of chemotherapeutic drugs 49. There
are reasons to believe that selenium may also make hydrogen
peroxide more lethal to tumors. We now administer selenium in
a form known as methylselenocysteine (MSC), which is a natural
organic form found in certain foods. MSC is the preferable form
for this application because it is rapidly metabolized to release
the organic selenium metabolites useful in cancer therapy. We
also will be exploring the use of activated vitamin D (calcitriol)
as a chemosensitizing agent in cancer therapy.
Dont Be Confused
Controlled clinical studies that show that vitamin C therapy
does not work in cancer only assessed oral vitamin C therapy 11.
As noted, oral vitamin C can achieve only very modest increases
in blood ascorbate levels. Intravenous vitamin C therapy has far
greater credibility, and indeed is currently being formally evaluated
in clinical trials at the U.S. National Institutes of Health.
6
Modulating Cellular Signal Transduction
Over the last several decades, molecular biology has
gradually been unraveling the way in which the bodys cells
work. Signal transduction refers to the way in which cellular
proteins undergo small and usually reversible alterations in their
structure to induce alterations in cell behavior. For example,
the catalytic activities of many enzymes are altered through a
process known as phosphorylation. In this process, phosphate
groups are attached to specific amino acids usually serine or
tyrosine. The enzymes which attach phosphate groups to proteins
are known as kinases. Their activity is opposed by another
group of enzymes, phosphatases, which remove phosphate
groups from proteins. Oftentimes, kinases and phosphatases
are themselves susceptible to phosphorylations that change
their activities 1. Another common way in which the functional
properties of cellular proteins are altered is by oxidation.
Oxidant stress can lead to the production of hydrogen peroxide,
which can interact with certain cysteine amino acids in proteins
to change their functional properties 2,3. These alterations can be
reversed by another group of enzymes known as reductases.
These considerations may sound very abstruse to someone
who hasnt had a chance to study molecular biology, but they
have very practical implications for the way cells behave. For
example, hormones which bind to cellular receptors often induce
these receptors to undergo self-induced phosphorylations of
tyrosines in these receptors.
This in turn sets off a chain reaction of alterations in the
structures of many proteins that can trigger cellular multiplication
or migration, and that can make the cells harder to kill with
cytotoxic chemotherapy or radiation 4. Moderate levels of
intracellular oxidative stress often act to reinforce these changes,
by causing temporary inhibition of phosphatases that remove
tyrosine phosphate groups.
Cancer cells are distinguished by the fact that, owing
to mutagenic alterations in their DNA, or so-called epigenetic
(potentially reversible) changes in their DNA structure, the
amount of certain proteins made by these cells is increased or
decreased, and/or the structure of these proteins is altered in
ways that influence their function 5. In cancer, the net impact
of these changes is to boost the activity of signal transduction
mechanisms that support cellular multiplication, tissue invasion,
and metastasis to distant organs, and that protect the cells from
being killed by radiation or chemotherapy. Often, cancer cells
express increased amounts of cell receptors, phosphorylate
tyrosines, or make mutant receptors that are constantly active
in this regard 6-8. The pro-growth, pro-survival impacts of these
receptors are often amplified by increased oxidant stress in cancer
cells, which prevents phosphatase enzymes from turning off the
signals triggered by these receptors 9,10.
One of the goals at Oasis of Hope is to use nutrients,
phytochemicals, and currently available drugs to suppress signal
transduction pathways that are overactive in cancer cells, or boost
pathways that are underactive. The intent is for cancer cells
to grow slower, make them aggressive, or make them easier to
destroy.
7
Oxidative Pre-conditioning Therapy:
Ozone and UV Light
When most people hear the word ozone, they think of a
protective layer of the atmosphere but arent really sure what it
is beyond that. Ozone is oxygen but with the molecular structure
O3 instead of O2. This additional molecule makes ozone a highly
reactive oxidant. If inhaled, ozone can do some serious damage to
our bodies. However, there is an application of this substance that
is very therapeutic. But first, lets take a closer look at ozone.
In nature, ozone has a good side and a bad side. In the
stratosphere, it acts as a shield, deflecting harmful UV irradiation.
However, in the troposphere, ozone is a major component of the
smog that harms humans, animals, and plants. When we breathe
it, ozone can cause serious pulmonary and systemic side effects
because it is such a powerful oxidant.
On the world scene, ozone therapy became an innovative
medical approach in 1954, when Wehrly and Steinbart first
described its application. They found that while the human
respiratory tract reacts very negatively to ozone, human blood does
not. In fact, when exposed to appropriate ozone concentrations,
our blood tames the strong oxidant properties of ozone, thus
eliminating any acute side effects. The benefits derived from this
therapy are staggering.
The ozone autohemotherapy (O3-AHT) standard technique
is to withdraw 150-200 ml of blood and expose it to an oxygen/
ozone mixture at a specified ozone concentration, followed by
intravenous reinfusion of this blood into the patient.
8
The IRT Anti-Inflammatory Therapies
The Oasis of Hope IRTs make use of three antiinflammatory drugs, each of which has been in use for decades:
salsalate, disulfiram, and diclofenac. These drugs are used
to target key proteins that, in many cancers, promote cancer
growth and spread while inducing resistance to chemotherapy or
radiotherapy.
Pro-inflammatory Factors
One of these targets is known as NF-kappaB. This protein
complex regulates the synthesis of a number of other proteins by
binding to DNA in the cellular nucleus. In a high proportion of
advanced cancers, NF-kappaB is either continuously activated or
is rapidly activated in response to chemotherapy 1-5. One of the
most important roles of NF-kappaB is to boost the production of
a number of proteins that act in a variety of ways to prevent the
process of apoptosis. This is the cell suicide process that is
the most common way in which cytotoxic anti-cancer drugs kill
cancer cells 6. Moreover, NF-kappaB also increases production
of a multi-drug resistance membrane protein that functions to
pump various cytotoxic chemicals, including many anti-cancer
drugs, out of cells 7. For these reasons, NF-kappaB activation,
either chronic, or triggered by chemotherapy, tends to protect
cancer cells during chemotherapy. Conversely, many studies show
that inhibitors of NF-kappaB activity can make resistant cancer
cells much more sensitive to chemotherapy and/or radiation 8-11.
Chronic activation of NF-kappaB also makes cancers
act more aggressively. This reflects: increased production of
Salsalate
Fortunately, several drugs are available which can suppress
the activity of either NF-kappaB or cox-2. One of these is salicylic
acid, a natural compound found in white willow bark that has
been used for many decades to treat inflammatory disorders such
as rheumatoid arthritis. In the late nineteenth century, German
chemists first synthesized aspirin (acetylsalicylic acid) by adding
an acetyl group to salicylic acid. Salicylic acid, like aspirin, can
inhibit cyclooxygenase enzymes, but its activity in this regard is
very weak and reversible, for which reason salicylic acid doesnt
produce the dangerous side effects sometimes seen with chronic
use of aspirin or related drugs, such as bleeding stomach ulcers or
kidney damage 25-27. It is now known that the anti-inflammatory
effects of high-dose salicylic acid are more likely to reflect
inhibition of NF-kappaB activation. Salicylic acid binds to
and inhibits an enzyme that is usually required for NF-kappaB
activation 28,29.
Although pharmaceutical companies are working
feverishly to develop expensive new inhibitors of NF-kappaB,
few medical scientists have considered the possibility of using
natural, inexpensive salicylate in cancer therapy 30. There is,
however, recent research establishing that salicylate has cancerretardant and anti-angiogenic activity. At Oasis of Hope, we
believe that salicylic acid has considerable potential for use in
cancer therapy, to potentiate the efficacy of chemotherapy in
certain cancers, to slow the growth and spread of cancer during athome therapy, and to slow or prevent the progression of cachexic
muscle degeneration 31,32.
Several pharmaceutical forms of salicylic acid are
available. We have chosen to use salsalate, a complex which is
broken down in the intestinal tract to release free salicylic acid,
which is then absorbed 33.
Salsalate is less likely to induce gastric irritation that
other forms of salicylic acid. It was developed in Japan about
50 years ago, and has been in use since that time for treatment
of inflammatory disorders. Salsalate wont produce dangerous
toxicity when used as directed. However, in optimally effective
anti-inflammatory doses, it can produce reversible ear dysfunction
tinnitus and mild hearing loss 34. Fortunately, these problems
resolve as soon as the drug is discontinued, and no permanent
damage is done. For the occasional patient in whom these side
effects are highly troubling, a dosage reduction can often solve
the problem. It is necessary to use these high doses to achieve
effective inhibition of NF-kappaB.
Disulfiram
Another drug with potential for inhibiting NF-kappaB
is disulfiram the drug more commonly known as Antabuse.
This drug was developed many years ago to help alcoholics
abstain from alcohol. If they drink alcohol while using Antabuse,
they become ill, owing to increased blood levels of the alcohol
metabolite acetaldehyde. More recently, it has been discovered
that disulfiram can inhibit cellular components known as
proteasomes 35,36. Proteasomes are responsible for degrading
cellular proteins which have been specifically targeted for
degradation. They play a crucial role in the activation of NFkappaB by degrading a protein that inhibits this activation. Thus,
inhibition of proteasome function usually decreases NF-kappaB
activity 37. Recent studies show that disulfiram and related sulfurcontaining compounds can inhibit proteasomes and thereby
suppress NF-kappaB activity in cancer cells. This renders them
less aggressive and more susceptible to eradication 36. In usual
clinical doses, disulfiram is a reasonably well tolerated drug as
long as the patient does not drink any alcoholic beverage. The
dose-limiting toxicity is gastrointestinal upset.
Diclofenac
With respect to cox-2, there are many drugs, commonly
referred to as NSAIDs, which can inhibit this enzyme. Some
of these drugs are relatively selective to cox-2 including the
prominently advertised drugs Vioxx and Celebrex. In other words,
these drugs have little impact on the other form of cyclooxygenase
(cox-1). Prolonged effective inhibition of cox-1 can lead to serious
complications such as bleeding stomach ulcerations and kidney
damage. For that reason, pharmaceutical companies developed
cox-2-specific inhibitors for use in the treatment of inflammatory
disorders.
Instead of using the expensive, highly advertised and
relatively new cox-2-specific inhibitors Celebrex or Vioxx,
we at Oasis of Hope have decided to use a much older drug,
diclofenac. Diclofenac has an activity spectrum nearly identical
to that of Celebrex, producing effective inhibition of cox-2 in
concentrations that only modestly impact cox-1, but it is much
less expensive 38. When administered in standard clinical doses,
diclofenac is more effective than Vioxx at inhibiting cox-2 in the
human body 39. While diclofenac has recently been shown to
increase heart attack risk like other cox-2-specific inhibitors do
40
, we always use it in conjunction with low-dose aspirin, which
likely will largely offset that risk.
9
Metronomic Therapy
In 2000, two cancer research groups published a
remarkable observation, in tumor-bearing rodents, low-dose
chemotherapy, too low to evoke side effects or have a meaningful
direct impact on tumor cells, when given on a daily or near-daily
schedule, could markedly retard tumor growth 1,2. This proved to
be true even when the tumors were known to be resistant to the
chemotherapeutic drugs employed. The solution to this riddle was
that the chemotherapy was slowing or preventing angiogenesis.
During angiogenesis, new endothelial cells are extremely
fragile as they branch off from existing blood vessels, multiply,
migrate into a tumor in response to chemical signals secreted
by tumor cells, and eventually form themselves into tubular
structures to give rise to new vessels. Whereas the endothelial
cells lining established vessels only rarely multiply, are stabilized
by growth factors provided by neighboring cells, and are rarely
killed by clinically feasible doses of chemotherapy drugs. The
endothelial cells engaged in angiogenesis are extremely sensitive
to killing by these drugs, much more so than most cancer cells.
Thus, when low-dose chemotherapy is administered on a daily
schedule (known as metronomic because it is regular and even
like the beat of a metronome) the continual death of endothelial
cells attempting to form new blood vessels can substantially
disrupt the angiogenic process, slowing it down notably.
One of the particular merits of this metronomic approach
centers around cancer drug resistance. Whereas conventional,
high-dose chemotherapy tends to select tumor cells that are
resistant to the drugs used, metronomic chemotherapy targets
normal endothelial cells that do not grow resistant to the drugs.
In other words, metronomic chemotherapy keeps on
working when conventional therapy fails. Tumors may be able to
adapt to a degree by increasing their production of pro-angiogenic
factors that promote endothelial cells survival. This explains
why cancers, which initially regress in response to metronomic
therapy sometimes grow back despite continuing therapy. The
cancer confers this relative resistance; not the endothelial cells
themselves.
Recently, a further benefit of metronomic chemotherapy
has been established. It tends to selectively kill a population of
immune cells, called T-reg cells, that function to suppress the
activity of immune cells capable of attacking the tumor. These
are the natural killer (NK) cells and T-cytotoxic cells 3. T-reg cells
often congregate within tumors and secrete hormone-like factors
that turn off the immune cells trying to attack the cancer. Thus,
metronomic chemotherapy has emerged as a useful adjuvant to
therapeutic strategies intended to boost the tumor-killing capacity
of NK and T-cytotoxic cells 4,5.
The utility of treating rodent tumors, including transplanted
human tumors, with metronomic chemotherapy has now been
confirmed in a great many studies 6,7. In some of these studies,
combining such chemotherapy with other measures attacking the
angiogenic process has led to complete remissions of pre-existing
aggressive tumors 2,8. Other studies also showed that metronomic
chemotherapy can be useful when used in conjunction with
conventional chemotherapy 9.
The most extensive published clinical experience
with metronomic chemotherapy regimens has been provided
by oncologists in Milan, who have documented the longterm responses of patients with metastatic breast cancer to a
metronomic regimen involving daily cyclophosphamide (50mg)
and two weekly doses of methotrexate (5mg per dose) 10,11.
From the patients using this regimen, 32% achieved
either a complete or partial remission, or a stabilization of disease
lasting at least 24 weeks. In about 16% of patients, no tumor
progression was noted for over a year. Even in the patients in
whom progression did occur, it seems likely that the therapy was
often slowing the spread of the disease. The especially good news,
since metronomic chemotherapy is intended for long-term use, is
that this regimen was essentially free of annoying side effects.
Only a mild suppression of white cell count was observed in a
small minority of the treated patients.
Since metronomic therapy is directed against endothelial
cells, not cancer cells, a metronomic regimen that works well
with one type of cancer should work well with all types of cancer
dependent on angiogenesis for growth. At Oasis of Hope, we use
a metronomic regimen like that tested by the Milanese doctors.
It is based on cyclophosphamide, also known by its trade name
Genoxal. We also include methotrexate for selected patients.
The Oasis of Hope IRT at-home protocols include
additional agents intended to slow the process of angiogenesis.
These include salsalate, silymarin, fish oil, the glycine in GPG,
and the green tea polyphenols in Synerpax. Thus, we are
attacking angiogenesis from as many angles as we feasibly can.
10
IRT Nutraceuticals for Cancer Control
At Oasis of Hope, we employ a broad spectrum of safe
nutraceuticals. They are used as components of the in-hospital
therapy and for continuing use when patients return home.
These agents are intended to modulate cell signaling pathways
in ways that should provide a diverse array of benefits such as
sensitizing cancers to cytotoxic chemotherapies or intravenous
vitamin C, slowing the growth of tumors, blocking the process of
metastasis, inhibiting the angiogenic response required for tumor
growth, boosting or disinhibiting the immune systems capacity
to attack the cancer, protecting normal tissues from the toxicity of
chemotherapies, and helping to control so-called paraneoplastic
syndromes that erode bones or decrease muscle mass. Here are
the chief nutraceuticals we use with the explanation of why and
how they are used.
Melatonin
Melatonin is a natural hormone produced primarily by the
pineal gland at the base of the brain. Secretion of melatonin is
regulated by light exposure. Also, a burst of melatonin secretion
occurs at nighttime during the onset of sleep. One of the primary
roles of melatonin is to synchronize endocrine and nervous system
rhythms in line with day-night cycles. For this reason, melatonin
is traditionally given at bedtime so that natural biorhythms are
reinforced rather than disrupted.
Melatonin exerts a range of physiological effects, some of which
are of direct relevance to cancer therapy.
Of particular interest is its ability to boost the function
of NK cells and helper-T lymphocytes. These components of
the immune system can help to control the growth and spread
of many tumors 1,2. NK cells usually have little impact on large
pre-existing tumors, but they do a better job of controlling the
small nests of tumor cells that can give rise to new metastases 3,4.
NK cell activity tends to decline as people age. This is at least
partially attributable to the fact that the pineals production of
melatonin tends to decline during the aging process 5.
Melatonin also functions as a major antioxidant. Although
melatonin itself can function as a free radical scavenger, this effect
is probably of little physiological significance because natural
concentrations of melatonin are quite low. The major impact
of melatonin on antioxidant defenses reflects its ability to boost
the production of many antioxidant enzymes in many tissues
6,7
. This antioxidant effect of melatonin can provide protection
when cancer patients receive cytotoxic drugs that can damage
healthy tissues by inducing oxidant stress. In experimental
studies, melatonin administration has been shown to lessen
the adverse effects of drugs such as doxorubicin and cisplatin,
without lessening the therapeutic impact of these drugs 8-11. The
heart, kidneys, and peripheral nervous system are among the vital
organs that melatonin protects.
Melatonin also functions to support the growth and survival
of bone marrow cells that give rise to circulating neutrophils,
lymphocytes, monocytes, which are immune cells, and platelets,
which are required for proper blood clotting. It apparently does
this by boosting the marrows production of certain key growth
factors 12,13. This effect is of evident relevance to cancer therapy
since many cytotoxic cancer drugs are highly toxic to the bone
marrow. The resulting decline in blood levels of white cells or of
platelets can increase risk for infection or bleeding complications,
and may require chemotherapy to be terminated or postponed.
Fish Oil
Fish oil is a uniquely rich source of the long-chain omega-3
fatty acids EPA(eicosapentaenoic acid) and DHA(docosahexaenoic
acid). A small structural difference distinguishes these fatty
acids from the omega-6 fatty acids found in plant-derived oils.
Within our bodies, a portion of ingested omega-6 fatty acids are
converted to the compound arachidonic acid. This in turn is the
precursor for a wide range of hormone-like compounds, known
as prostanoids, that play a key role in inflammatory processes.
EPA and DHA are very similar in structure to arachidonic acid,
and, when consumed in adequate amounts, they can act in various
ways to antagonize the production of active prostanoids. For this
reason, diets rich in fish oil tend to have anti-inflammatory effects
in rheumatoid arthritis and certain other chronic inflammatory
disorders20. Furthermore, one of the prostanoids whose production
is antagonized by fish oil is thromboxane, which plays a role in
blood clot formation by promoting aggregation of the platelets.
This discovery led to speculation that the relatively low risk for
heart attack among aboriginal Eskimos may reflect their high
consumption of seafood rich in EPA and DHA 21. Also, omega-3
fats reduce the risk to develop dangerous cardiac arrhythmias.
EPA and DHA have a valuable role to play in cancer treatment.
A number of studies show that a diet rich in fish oil tends to slow tumor
growth 22-25. At least part of this effect can be attributed to a suppressive
effect of fish oil on angiogenesis. Remember that angiogenesis is the
process by which new blood vessels develop to enable the growth and
spread of tumors 24-27. EPA has been shown to decrease the expression
of a key receptor required for response to the pro-angiogenic compound
vascular endothelial growth factor (VEGF) 28.
Another key factor in angiogenesis is the enzyme Cox-2, which
produces prostanoids required for vascular tube formation during the
angiogenic process 29.
A high intake of fish oil has the potential to antagonize the role of
Cox-2 in the angiogenic process by decreasing the production of
Cox-2-derived prostanoids.
Fish oil also has the potential to act directly on tumor cells
to slow their proliferation. In some tumors, prostanoids produced
by Cox-2 or other enzymes known as lipoxygenases can promote
the multiplication and spread of cancer cells and/or protect them
from apoptosis 30,31. Fish oil can antagonize the pro-proliferative
activity of these prostanoids by suppressing their synthesis.
Fish oil has the ability to fend off cachexia, the severe
loss of muscle mass that often complicates late-stage cancer
32-35
. Although cachexia usually entails a loss of appetite that can
contribute to weight loss by decreasing calorie intake, the lifethreatening selective loss of muscle mass often seen in cancer
reflects a very specific inflammatory process in muscle fibers that
is not seen in healthy dieters. It has been discovered that EPA
interferes with the inflammatory mechanisms that cause loss of
muscle mass.
Finally, a number of experimental studies demonstrate
that fish oil, particularly DHA, can boost the responsiveness
of cancer cells to chemotherapy and radiotherapy 36,37. The
mechanism of this effect is not well understood, but it is suspected
that DHA, which is polyunsaturated and highly susceptible to
oxidative damage, serves to amplify oxidative stress in cancer
cells assaulted by cytotoxic chemicals or radiation. Cell culture
studies suggest that normal healthy cells are less susceptible to
this sensitizing effect of DHA for reasons that remain unclear.
The potential impact of DHA on response to chemotherapy is one
reason why fish oil is included in the in-hospital supplementation
regimen for cancer patients at Oasis of Hope.
Most of us have a lot of fat in our bodies, including the omega-6
fats for which EPA and DHA serve as functional antagonists.
For that reason, it usually takes at least several months
for fish oil intake to achieve its maximal physiological effects.
The ratio of omega-3 to omega-6 in the bodys tissues is a key
determinant of the efficacy of fish oil supplementation. A given
daily dose of fish oil will presumably have a greater and faster
impact in people who are maintaining their total daily fat intake
low.
In summary, the ample EPA/DHA intake provided with
the Oasis of Hope IRT protocols is intended to: suppress the
angiogenic process required for the growth and spread of tumors;
act directly on some susceptible cancers to slow their proliferation;
help prevent loss of muscle mass (cachexia); and improve the
responsiveness of cancers to certain chemotherapeutic agents or
radiation.
Vitamin D
Growing evidence confirms that good vitamin D status
not only decreases risk for many prominent cancers, but also can
improve the results of chemotherapy and lengthen survival in
people who already have cancer. Vitamin D is often called the
sunshine vitamin because the skin manufactures it when rays
of ultra violet (UV) light interact with a cholesterol precursor in
the skin. The resulting compound is then quickly transformed in
the liver to a derivative, calcidiol, which circulates in the blood.
Calcidiol can also be produced from vitamin D obtained from
supplements or foods. Calcidiol, per se, has little physiological
activity. In order to do its metabolic job, calcidiol must be further
transformed to calcitriol, which can bind to vitamin D receptors
in the nucleus of cells. Most of the calcitriol found in the blood is
produced in the kidneys.
Just within the last few years, scientists have learned
that many types of epithelial cells (type of cells that give rise to
most of the dangerous solid tumors) are capable of converting
In other words, people who have spent most of their lives
in sunny regions, tend to be at lower risk for cancer than people
who live in northern latitudes. It has been estimated that sub
optimal UV exposure is responsible for over 23,000 premature
cancer deaths per year in the U.S. alone 38,49. The types of cancer
whose risks are influenced by vitamin D status include cancers of
the breast, colon, rectum, ovary, prostate, pancreas, stomach, and
uterine endometrium, as well as non-Hodgkins lymphoma.
But what does this have to do with therapy of pre-existing
cancers?
Fortunately, some of the cancers that arise from
epithelial cells capable of making calcitriol retain the capacity
to make calcitriol and express vitamin D receptors 38,50. In these
cancers, an increase in blood levels of calcidiol, achieved by better
UV exposure or supplemental vitamin D, leads to an increased
production of calcitriol in the tumor. This calcitriol can slow
the proliferation of the cancer cells while increasing their ability
to commit suicide 51-53. Moreover, the impact of calcitriol on
capacity for apoptosis can sometimes render these cancers more
susceptible to cytotoxic chemotherapy or radiotherapy 54-57.
Recently, epidemiologists around the world have noted
that cancer patients diagnosed during summer typically survive
longer than patients diagnosed in winter 58-60. This presumably
reflects the fact that, in those cancers still capable of making
calcitriol, the relatively good vitamin D status during summers
renders the cancers more sensitive to chemotherapy and/or slows
the growth of the cancer. At Oasis of Hope, we make sure that our
patients are being treated in summer by giving them 10,000 IU
of vitamin D daily.
One pioneering study from Toronto has examined the
influence of supplemental vitamin D (2,000 IU daily) on prostate
cancer patients whose PSA levels remained measurable following
surgery or radiotherapy 61. During this supplementation, the rate of
tumor growth, assessed by PSA measurements, slowed markedly
in 14 of the 15 subjects enrolled in the study.
Silibinin
Milk thistle extract has been used for many decades
in the treatment of liver disorders. Approximately 80% of this
extract consists of silymarin, a mixture of several compounds
known as flavonolignans. Silibinin, the most prominent of these
compounds, accounts for about 60% of the weight of silymarin,
and is believed responsible for most of the liver-protective activity
of silymarin and milk thistle extract. Just within the last decade,
scientists have learned that silibinin has considerable potential
for preventing and treating cancer.
In concentrations that may be feasible to achieve with
high-dose clinical regimens, silibinin has been shown to have
growth inhibitory effects on a wide range of human cancer cell
lines including cancers arising from the prostate, breast, colon,
lung, liver, bladder, and cervix 62-69. Silibinin can suppress the
proliferation of these cells, while at the same time increasing
the rate at which they die by apoptosis. In addition, silibinin
can sensitize cancer cell lines to the killing effects of certain
cytotoxic chemotherapeutic drugs 70. Thus, silibinin may have
potential both for retarding the growth and spread of cancer and
for boosting the response of cancers to chemotherapy.
The mechanisms responsible for these effects have been
studied most intensively in human prostate cancer cells 71. It
should first be noted that these studies show that concentrations
of silibinin, which retard the growth of these prostate cancers, do
not influence the growth of cells from healthy normal prostate. In
other words, the effects of silibinin on cell proliferation appear
to be specific to cancer cells. The anti-proliferative effects of
silibinin on prostate cancer cells have been traced to decreased
function of the epidermal growth factor receptor (EGF-R).
This is a key mediator of growth signals in prostate
cancer and in many other types of cancer 72. Silibinin binds to
this receptor and prevents it from interacting with hormones
that activate it. Some of these are produced in prostate cancers.
Furthermore, silibinin induces prostate cancer cells to make more
of a compound, known as IGFBP-3, that binds to and inhibits
the activity of insulin-like growth factor-I (IGF-I), a key growth
factor for many cancers 73.
Silibinin has also been shown to decrease the activation
of NF-kappaB 74,75, a protein complex that, when activated, tends
to make cancer cells more aggressive and renders them less
sensitive to chemotherapy or radiotherapy 76,77. In many prostate
cancers, and indeed in many other types of cancer, NF-kappaB
is continuously active. The effect of silibinin on NF-kappaB
helps to rationalize silibinins ability to increase the sensitivity of
cancers to certain chemotherapy drugs. The effects of silibinin
on growth factor signals, which promote cancer cell survival, also
contribute in this regard.
The impact of orally administered silibinin on the growth
of human tumors in immunodeficient mice has been studied with
three different types of tumor prostate, lung, and ovarian 78,79.
In each case, silibinin has been found to have a substantial and
dose-dependent suppressive effect on tumor growth in doses that
had no apparent toxicity to the treated animals.
Examination of the silibinin-treated tumors revealed that
they had a much less developed vasculature than control tumors.
In other words, there were less blood vessels in the tumor to
provide nourishment and oxygen 78,79.
Follow-up studies showed that in some cancers silibin
could suppress secretion of a compound known as vascular
endothelial growth factor (VEGF), which plays a key role in
inducing the growth of new blood vessels into tumors 78,80,81.
Furthermore, other studies show that clinically feasible
concentrations of silibinin have a direct effect on endothelial
cells. Silibinin can suppress the proliferation of these cells and
reduce their ability to migrate, invade tissues, and roll themselves
into tubes, which is how new blood vessels are formed 74,80. These
findings suggest that the growth-slowing impact of silibinin on
tumors reflects the interaction of at least three phenomena: a
direct anti-proliferative effect on cancer cells; a suppression of
VEGF production by these cells; and a direct inhibitory effect on
the capacity of endothelial cells to build new blood vessels.
Selenium
The use of selenium in cancer therapy is motivated, in part, by
substantial evidence that good selenium nutrition can reduce
cancer risk 82. Dr. Larry Clark, and colleagues, conducted a massive
double blind clinical study that recruited over 1,300 American
subjects known to be at high risk for skin cancer, but free of any
serious cancers at the time of enrollment 83. For over a decade,
these volunteers received either selenium (200 mcg daily) or a
matching placebo. Although the supplemental selenium failed
to reduce subsequent risk for skin cancer, the researchers were
encouraged to find that the cancer death rate in the seleniumsupplemented group was only half as high as that in those receiving
the placebo, 29 vs. 57. Indeed, the researchers were forced to
terminate the study earlier than planned, as they considered it
unethical to continue with the placebo supplementation. The
lower cancer death rate in the selenium group was primarily
attributable to a substantial reduction in the i incidence of new
serious cancers in the lungs, colon, and prostate84,85.
Epidemiological studies have also pointed to decreased
risks for certain cancers in people who have relatively high
Synerpax
Synerpax is a multi-ingredient nutritional supplement
used in conjunction with both the in-hospital and at-home IRT
regimens. It provides a blend of phytochemicals: green tea
polyphenols, curcumin, piperine, resveratrol, and grape seed
extract. These have demonstrated cancer retardant efficacy.
Synerpax also includes Selenium and Zinc, which are important
elements in the fight against cancer.
Curcumin
Another intriguing phytochemical supplied by Synerpax
is curcumin the agent that makes turmeric yellow. Curcumin has
slowed growth, promoted cell death by apoptosis, and increased
responsiveness to chemotherapy drugs in a wide range of cancer
cell lines 97-101. Oral curcumin may indeed prove to have value
for prevention of colon cancer 102, which reflects the fact that
curcumin taken up by the mucosal cells lining the colon can exert
a worthwhile effect in these cells before it is metabolized.
Piperine
To expedite the absorption of curcumin and perhaps other
constituents of this supplement, Synerpax includes piperine,
also known as Bioperine. It is a compound found in black
pepper. Piperine has been shown to enhance the absorption
of numerous phytochemicals and drugs, in part because it is a
potent inhibitor of a protein pump that pushes a wide range
of chemicals out of intestinal cells 103. A clinical study assessing
absorption of curcumin found that concurrent administration
of piperine improved absorption about 20-fold 104. A favorable
effect on piperine on absorption of EGCG in mice has also been
reported105.
Resveratrol
Resveratrol is an antioxidant phytochemical found in
red wine. Resveratrol, like curcumin, has potential to block the
activation of NF-kappaB, a protein complex that makes many
cancers more aggressive and resistant to chemotherapy 108.
Zinc
A nutritional dose of zinc is included in Synerpax since
this mineral plays a key role in effective function of the immune
system. It is desirable to insure that the zinc nutrition of cancer
patients is at least adequate 109.
Boswellic Acids
Boswellic acids are a group of closely related compounds
found in salai guggul, a resinous extract from the tree Boswellia
carteri traditionally used in Ayurvedic (Indian) medicine as
an anti-inflammatory agent 110. In the early 1990s, German
researchers discovered the mechanistic basis for salai gugguls
anti-inflammatory efficacy. Boswellic acids are very potent
inhibitors of the enzyme 5-lipoxygenase (5LPO), which plays an
essential role in the generation of a family of hormone-like proinflammatory compounds known as leukotrienes 111.
There is increasing evidence that 5LPO is often expressed
by many types of cancer, and that this enzyme generates
compounds that have potent growth factor activities for these
cancers 112-114. Inhibiting 5LPO typically retards the growth of
cancer cell lines dependent on 5LPO, and often increases the rate
at which these cells die by apoptosis. Human cancer cell lines
derived from prostatic, pancreatic, breast, esophageal, colorectal,
bladder, gastric, and renal cancers, as well as mesotheliomas and
leukemias, have shown 5LPO dependency 115-122. Not all such
cancers are 5LPO dependent.
The impact of 5LPO activity on the sensitivity of cancers to
chemotherapy or radiotherapy has so far received little attention.
However, one fascinating recent report indicates that, concurrent
expression of 5LPO is associated with substantial protection from
the cytotoxicity of chemotherapeutic cancer drugs 123.
Conversely, suppression of 5LPO in these cancers greatly
enhances their sensitivity to these drugs. This implies that 5LPO
inhibitors, administered prior to and during chemotherapy,
should enhance the responsiveness of a high proportion of human
cancers.
Zileuton, a drug approved for treatment of asthma, works
by inhibiting 5LPO, and has shown cancer-retardant activity
in hamsters with pancreatic cancer 124. However, we have
chosen to use boswellic acid-rich extracts in Oasis of Hope IRT
regimens because they are considerably less expensive and can
be presumed to be safe based on centuries of use in traditional
medicine. Moreover, a number of cell culture studies indicate
that boswellic acids, most notably one known as acetyl-11-ketobeta-boswellic acid, can slow the proliferation and boost the death
rate of various human cancer cell lines 125-129. The only published
clinical experience with boswellic acids in the treatment of cancer
dealt with the use of these agents in patients with progressing
brain cancers 130,131. Although some of the children experienced
improved neurological function during this treatment, this
might have reflected an anti-inflammatory effect of leukotriene
suppression rather than tumor regression. Nonetheless, the
observed benefit was worthwhile. In rats transplanted with
gliomas, treatment with boswellic acids could more than double
survival time 132. In the in-hospital IRT protocol and at-home
regimen, we include a potent dose of boswellic acids.
GPG
GPG is a nutraceutical, developed by Oasis of Hope
scientists, that features Glycine, Modified Citrus Pectin and
Glutamine. Recent research has demonstrated that these three
active ingredients have the potential to: slow the growth and
Glutamine
The last ingredient of GPG is the amino acid glutamine.
This amino acid serves as an important source of food calories for
immune cells as well as the gastrointestinal tract. Skeletal muscle
constantly generates and exports glutamine to aid the nutrition of
these tissues 142.
Glutamine also has the potential to protect immune
and gastrointestinal cells from damage by radiation and/or
chemotherapy 143-145. A recent study observed that supplemental
glutamine helps the white blood cell count (neutrophils) to
recover faster following chemotherapy 146.
The potential benefits of supplemental glutamine to cancer
patients are multi-faceted: reducing some of the dangerous side
effects of radiation and/or chemotherapy, without protecting
tumor cells 143-147; boosting the capacity of natural killer cells to
attack the tumor, thereby helping to control the spread of cancer,
particularly new metastases; and helping to prevent the severe loss
of muscle mass (cachexia), a common complication of advanced
cancer.
Biotin
Most tumors have a rather haphazard blood supply
that leaves some regions of the tumor poorly perfused and low
in oxygen. It has long been known that when cancer cells are
in a hypoxic environment, they tend to be less sensitive, not
only to radiotherapy, but also chemotherapy. The basis of this
phenomenon has not been fully clarified, but scientists recently
have proposed an intriguing explanation 148-151. Most tumors
generate a gaseous compound known as nitric oxide, which has
a range of important physiological effects. Synthesis of nitric
oxide can be substantially reduced in hypoxic tumor regions,
11
IRT Nutraceuticals for Specific Cancers
Not all cancers are alike. Each type of cancer has its
own special properties. Thats why some phytonutrients have the
potential to aid control of certain cancers, but not others. Thus,
the Oasis of Hope IRT regimens include some agents that are used
only for the treatment of one or several specific cancers. Agents
that fall into this category include soy isoflavones, lycopene,
pomegranate extract, coenzyme Q10, resveratrol, curcumin, and
biotin.
Soy Isoflavones
There are two types of estrogen receptors: alpha and
beta 1. The alpha form of the receptor (ERalpha) tends to have
growth promotional activity in tissues that express it. Thus, when
estrogens activate ERalpha in breast or the uterus (endometrium),
they promote proliferation and increase the risk that a cancer will
arise in the stimulated tissue. Once a cancer does arise, estrogens
tend to support the growth and survival of the cancer cells at
least until the tumor evolves to estrogen independence. By
way of contrast, the beta form of the estrogen receptor (ERbeta)
tends to have anti-proliferative actions. In the tissues, which
express it, activation of ERbeta helps to prevent cancer, and, in
cancers which express ERbeta, its activation tends to slow cancer
spread and improve therapeutic response 2. There is, however, a
tendency for expression of ERbeta to decline as cancers evolve
over time. This adaptation likely reflects selection for more
aggressive cancer cells 3-5.
Epithelial cells of the colon, prostate, and ovary tissues that
express ERbeta are not usually thought of as estrogen responsive.
The cancers that arise from these tissues often continue to express
ERbeta, and can be controlled to some degree by estrogens which
activate ERbeta 6-12. While it is well known that postmenopausal
estrogen replacement therapy increases risk for breast cancer, it
is less appreciated that such therapy reduces risk for colorectal
cancer. This presumably reflects the protective activity of
ERbeta 13.
Using estrogenic drugs to control colorectal, prostate, or
ovarian cancers is a less than ideal proposition. Such hormones
would have feminizing effects in men and could increase risk for
breast or uterine cancer in women. Thus, it is extremely fortunate
that soy isoflavones preferentially activate ERbeta, in serum
concentrations that can feasibly be achieved by heavy ingestion
of soy products or the use of concentrated supplements, but that
have very little impact on ERalpha 1,2. Thats why soy-rich diets
dont feminize men, but still have phytoestrogen activity.
These considerations help to rationalize the numerous
epidemiological studies which conclude that people whose diets
are relatively rich in soy products are at lower risk for colorectal,
prostate, or ovarian cancer 14-16. They also help to explain why
diets high in soy or soy isoflavones tend to reduce the incidence of
these cancers in carcinogen-treated rodents 17-19. Such diets also
can inhibit the growth of transplanted human prostate tumors,
and/or render these cancers more sensitive to control by chemoor radiotherapy 20.
More importantly, several pilot clinical trials in men with
prostate cancer and steadily rising PSA values have shown that
soy isoflavones or a soy-rich diet can slow the rise in PSA in
some instances causing a moderate temporary reduction in this
biomarker 21.
Lycopene
The role for dietary lycopene in the prevention and
treatment of prostate cancer was first suggested by epidemiological
studies pointing to a decrease in risk for serious prostate cancer
in men who consumed an ample amount of tomato products 22.
Tomatoes are very rich in the carotenoid lycopene, and tomato
products represent the chief source of lycopene in most diets.
Subsequent studies showed that diets enriched in lycopene
could slow the growth of transplanted human prostate cancers in
mice 23. Moreover, two clinical reports from India indicate that
surprisingly modest daily doses of lycopene can reduce or slow
the rise in PSA in patients with metastatic prostate cancer 24,25. In
a Dutch controlled clinical study targeting patients with rising
PSA despite recent prostatectomy, a complex dietary supplement
featuring lycopene, soy isoflavones, silymarin, and antioxidants
was shown to slow the rate of PSA increase 26. All of these
neutraceuticals are included in Oasis of Hope IRT regimens for
prostate cancer. Another study showed that heavy consumption
of tomato products by patients scheduled for prostatectomy can
exert an antioxidant effect on the prostate, reducing the level
of oxidatively damaged DNA 27. This suggests that lycopene,
and perhaps other constituents in tomato sauce, may play a
physiologically important role in protecting the prostate from
oxidative damage.
Pomegranate Extract
The other tumor-specific nutraceutical that Oasis
of Hope uses with prostate cancer patients is pomegranate
extract. Although most pomegranate research has focused on
potential benefits for cardiovascular health, the possibility that
Coenzyme Q10
During the 1970s, the antioxidant nutrient coenzyme
Q10 (CoQ) began to attract attention as a possible adjuvant for
cancer therapy. This interest was prompted initially by several
studies showing that CoQ supplementation could boost the
function of macrophages, immune cells that help to recruit other
types of immune cells that can attack cancers 33,34. Subsequently,
physicians affiliated with CoQ expert Dr. Karl Folkers began to
employ CoQ, in doses as high as 390 mg daily, in the treatment of
patients with metastatic breast cancer. Several of these patients
were reported to experience complete or partial regression of
metastases while on CoQ therapy 35,36. In addition, a study found
that 38% of patients with metastatic breast cancer had serum
levels of CoQ that were abnormally low 37.
Resveratrol
Another nutraceutical potentially useful in breast cancer
is resveratrol. This phytonutrient, a key antioxidant in wine, is
included in Synerpax, and is discussed elsewhere in that context.
So far, the only type of transplanted human cancer that has been
shown to respond to resveratrol is breast cancer 38.
Curcumin
Another key ingredient of Synerpax is curcumin. This
phytonutrient seems likely to have its greatest impact on colorectal
or intestinal cancers that are still in their original location, not
having been removed surgically. Under these circumstances,
curcumin may be able to reach some of the cancer cells before it
has been extensively metabolized in the process of absorption.
Biotin
Oasis of Hope at-home supplementation for colorectal
cancer includes high doses of the B vitamin biotin. This is because
moderately high concentrations of this vitamin can activate
the enzyme guanylate cyclase, which produces an intracellular
regulatory compound called cyclic GMP (cGMP). Many studies
show that cGMP slows the rate of proliferation of colon cancer
cells, while increasing their tendency to commit suicide via
apoptosis. Increased production of cGMP also appears likely to
reduce risk for colorectal cancer. Why these beneficial effects
of cGMP appear to be specific for colorectal cancer remains
unclear.
12
IRT Specific Drugs for Cancer Control
Oasis of Hope IRT protocols, in addition to including a
range of anti-inflammatory adjuvant drugs, also include several
other drugs that usually are not considered anti-inflammatory.
These include the drugs cimetidine and valproic acid, each of
which has been used safely for decades. We also use drugs that
modulate sex hormone activities in patients who have hormonesensitive breast or prostate cancers. The following provides an
explanation.
Cimetidine
Cimetidine, also known as Tagamet, has been in wide
use for many years as a treatment for gastrointestinal ulcers. It
functions to suppress production of gastric acid by blocking socalled H2 receptors for the hormone histamine. In 1988, Danish
researchers reported that, in patients with gastric cancer, concurrent
cimetidine therapy was associated with improved survival 1.
Since then, cimetidine has been reported to improve survival
in patients with colorectal cancer 2,3 and occasional objective
responses have been observed in patients with melanoma or renal
cell cancer treated with cimetidine alone or in conjunction with
the anti-coagulant drug coumari. 4,5. Cimetidine has also shown
growth-retardant effects on certain cancers in rodents 6,7. It was
initially suspected that these benefits reflected a significant role
for histamine as an immunosuppressive or growth-stimulant
hormone in clinical cancer. However, cancer clinical studies
evaluating other anti-ulcer drugs that block H2 receptors failed
Valproic Acid
Valproic acid is a member of a class of drugs known as
histone deacetylase inhibitors that have recently shown versatile
anti-cancer effects in animal studies. Acetylation, in which
chemical structures known as acetyl groups are enzymatically
linked to proteins is often required for efficient transcription of
genes. Transcription is the process whereby nuclear DNA is used
as a template for production of messenger RNA which in turn
serves as a template for synthesis of new proteins. Acetylation
of DNA-binding proteins known as histones usually aids the
transcription of genes. Proteins known as co-activators promote
acetylation of histones near specific genes to promote their
transcription. However, it is sometimes physiologically desirable
to suppress gene transcription, so cells also produce enzymes
known as histone deacetylases (HDACs). As their name implies,
they remove the acetyl groups from histones and other acetylated
proteins.
In many cancers, anomalously decreased transcription
of certain genes, known as suppressor genes, contributes to the
malignant behavior of cancer. These genes code for proteins
that have anti-proliferative effects in the cell. Some years ago,
it occurred to cancer scientists that excessive or inappropriate
HDAC activity might be responsible for the suppressed
transcription of certain suppressor genes. They reasoned that,
if this were the case, drugs which inhibit HDACs might boost
the transcription of these suppressor genes and thereby make the
cancer less aggressive and more controllable. When they treated
cancer cells with chemicals that could inhibit HDAC, they were
gratified to observe that the cancer cells often decreased their rate
of multiplication, were more prone to apoptosis, and were easier
to kill with cytotoxic cancer drugs. In some cases, the drugs had
a redifferentiating effect, meaning that the cancer cells looked
and acted more like the healthy tissues from which they were
derived. In mice transplanted with human cancers, treatment with
HDAC inhibitory drugs slowed cancer growth and increased the
efficacy of cytotoxic chemotherapeutic drugs or radiotherapy 16-22.
However, the researchers were surprised to find that
increased expression of proteins coded by suppressor genes
usually was not clearly responsible for these benefits of HDAC
inhibitors. In fact, many proteins inside and outside the nucleus
are susceptible to reversible acetylation, and so HDAC inhibitors
may be influencing the structure and function of a great number
of regulatory cellular proteins by boosting their acetylation.
Why HDAC inhibition tends to have such a favorable effect
on the behavior of cancer cells remains unclear and is a subject
of active investigation. Perhaps one way to look at it is this:
the unregulated growth and relative invincibility of cancer cells
reflects a carefully balanced regulatory system. Treating with
HDAC inhibitors is rather like throwing a monkey wrench into
this mechanism, inducing an alteration of cellular behavior.
Fortunately, this alteration tends to be positive for the patient.
Moreover, HDAC inhibitors tend to be well tolerated, having
comparatively little impact on the function or viability of most
healthy tissues 23.
Remarkably, HDAC inhibitors also have anti-angiogenic
effects, acting directly on endothelial cells to slow the development
of new blood vessels required for cancer growth and spread
24-26
. These drugs can also suppress tumor production of certain
angiogenic factors, notably vascular endothelial growth factor
(VEGF), which are crucial stimulants to tumor angiogenesis
27
. This latter effect is at least partly attributable to decreased
activity of a protein (transcription factor) known as hypoxiainducible factor-1, which promotes the angiogenic process
in poorly oxygenated tumors 28,29. Yet a further benefit is that
Analogously, many prostate cancers require testosterone
to grow and thrive. This is especially true during the earlier
stages of the disease. Thats why medical science has developed
specific drugs that can inhibit the production or activity of these
sex hormones, for use in cancer therapy. This strategy has become
a standard part of cancer management, with well-documented
benefits for controlling cancer spread and prolonging patient
survival. So these hormone-blocking drugs are included in the
IRT protocols for hormone-dependent breast and prostate cancers.
The good news about these agents is that they dont have the
range of side-effects that cytotoxic chemotherapies have. The
unavoidable bad news about them is that loss of estrogen in women,
and of testosterone in men, can have undesirable physiological
effects. In particular, men lose sexual potency when deprived
of testosterone. Many of our patients with hormone-sensitive
prostate cancer choose not to use testosterone-blocking drugs. As
is always the case at Oasis of Hope, the patient is the final arbiter
regarding the therapy that he or she receives.
With respect to estrogen-sensitive breast cancers, our
therapeutic approach depends on whether the woman is pre- or
post-menopausal. In pre-menopausal women with estrogensensitive breast cancers, we standardly use the drug tamoxifen,
which binds to the estrogen receptor in a way that diminishes its
growth-promoting activity in breast cancers. Tamoxifen is known
as an estrogen antagonist, because it prevents estrogen from
binding to the receptors that mediate its hormonal activity. The
use of tamoxifen effectively entails the induction of menopause
in pre-menopausal women. This is unfortunate. But menopause
is part of the natural life cycle in any case, so most women learn
to live with this. Tamoxifen is generally considered a safe drug,
though its long-term use does increase risk for cancers of the
uterine endometrium.
In post-menopausal women, the ovaries are no longer
generating estrogens. Nonetheless, a certain amount of estrogen
is still produced in fat cells. Fat cells (adipocytes) contain an
enzyme called aromatase that can convert circulating androgens to
estrogen. Please note that healthy women normally produce very
small amounts of male hormones. Drugs known as aromatase
inhibitors can inhibit this fat-mediated conversion of androgen
to estrogen, and so can greatly reduce estrogen levels in postmenopausal women. They dont influence ovarian production of
estrogen in pre-menopausal women, and so arent used in premenopausal patients. Studies show that aromatase inhibitors do
a better job than tamoxifen for slowing or reversing the spread of
estrogen-sensitive breast cancers in post-menopausal women, so
this is the option which Oasis of Hope uses in the management
of estrogen-sensitive post-menopausal breast cancer 41. Several
different aromatase inhibitors are now available for clinical use
with generic names like anastrazole or letrozole. Since
it is not yet clear which of these drugs is clinically superior, our
doctors use their own judgment in choosing them. Aside from
the fact that these drugs induce a loss of estrogen activity, they
are well tolerated.
Years ago, the traditional therapy for testosteronedependent prostate cancer was a surgery known as orchiectomy,
which is the medical term for castration. Because this was a less
than popular option with most patients, pharmaceutical companies
have developed drugs that can inhibit the function or production
of testosterone, while allowing the patient to keep his testicles.
Not surprisingly, this strategy has proved much more popular,
and is the approach we recommend at Oasis of Hope.
Two drug-based strategies are commonly used for
suppressing testosterone activity in androgen-dependent prostate
cancer. One of these is to block the testosterone receptor with a
13
Surgery and Radiation Therapy at
Oasis of Hope
Localized tumor masses can often be effectively treated
by radiotherapy or surgical excision. Such measures are often
curative in early stage cancer, and can be used to relieve pain
or pressure in patients with more advanced disease. Like other
credible cancer clinics, Oasis of Hope uses surgery or radiotherapy
when they are warranted. But, unlike most other cancer clinics,
we use a variety of adjuvant measures that are intended to make
radiotherapy more effective, and surgery less traumatic.
Tumor cells are often hypoxic because the vascular
system feeding tumors tends to be haphazard and inefficient.
Unfortunately, effective cell killing by radiation requires the
presence of molecular oxygen, as this catalyzes the damage to
cellular DNA 1. Thus, hypoxic tumor cells can be less sensitive
to radiotherapy than are healthy normal tissues that are well
oxygenated. For this reason, Oasis of Hope employs several
adjunctive strategies intended to boost tumor oxygen content.
The oxygen-transporter Perftec, the anti-inflammatory agent
pentoxifylline, and ozone autohemotherapy work in various
complementary ways to: increase the oxygen content of the blood;
make red and white blood cells more distensible so that blood can
flow through tumors more efficiently; and increase the capacity
of red blood cells to deliver oxygen to tissues 2-5. These strategies
have a selective impact on the radiosensitivity of hypoxic tumor
regions, since increasing the oxygenation of healthy tissues that
14
Oasis of Hope Diet and Exercise
Throughout most of the twentieth century, age-adjusted
death rates for many of our most common cancers were vastly
lower in much of the Third World than in comparatively wealthy
industrialized countries such as the United States. These types of
cancers thus became known as Western cancers. They include
cancers of the breast, prostate, colon, ovary, uterine endometrium,
and pancreas cancers that, along with tobacco-induced lung
cancer, constitute the main causes of cancer mortality in the U.S.
today.
Why have these cancers been so less common in poorer
societies? The most reasonable current explanation seems to be
that, in poor societies, blood levels of two key growth factors
insulin and free insulin-like growth factor-I (IGF-I) tend to be
much lower than in wealthier countries 1,2. Insulin and/or IGF-I
stimulate the proliferation of the epithelial tissues from which
these cancers arise. They also inhibit the process of apoptosis,
which is an important way in which the body gets rid of cells which
have sustained mutagenic DNA damage 3. The combination of
increased proliferation which makes DNA damage more likely
and suppression of the mechanism that rids the body of mutated
cells, is a potent stimulus to cancer induction.
What aspects of a Western diet and lifestyle are primarily
responsible for our higher levels of insulin and free IGF-I? We
speak of free IGF-I because there are various proteins in the
blood that bind to IGF-I, rendering it inactive. Only the unbound
free IGF-I can interact with cell receptors. Factors such as
As noted, the relatively high levels of insulin and free
IGF-I characteristic of advanced societies can act directly on
their target tissues to promote cancer induction. They can also
act in indirect ways to boost cancer risk. In particular, this
pattern of hormone activity tends to accelerate sexual maturation
in girls and increase blood levels of free sex hormones 9,10.
These circumstances are known to increase risk for breast and
endometrial cancers. Obesity, per se, increases estrogen levels
in postmenopausal women, as fat cells are capable of producing
estrogen from other circulating steroid hormones 11.
Of course, at Oasis of Hope we are primarily focused on
treating cancer rather than preventing it. What is the relevance of
these considerations to cancer treatment? Insulin and/or free IGF-I
have growth factor activity for many, though not all, cancers. This
growth factor activity makes cancer cells multiply faster, increase
their capacity to spread throughout the body, evoke angiogenesis,
lessen their rate of spontaneous cell death, and render them less
sensitive to elimination by chemotherapy 12. In other words, if
a cancer is sensitive to either insulin or free IGF-I, a patients
prognosis will be better if the insulin and free IGF-I levels are
kept relatively low. Admittedly, some cancers arent responsive
to these hormones. Since there arent any simple inexpensive
tests that can determine this, its prudent to assume that a cancer
is responsive to these hormones.
Working with volunteers enrolled in the Pritikin dietexercise program, Dr. James Barnard and colleagues of UCLA
have done some studies that beautifully illustrate these points
13,14
. They took serum samples from patients who were about
to enroll in the program, and then took serum from the same
patients after they had been on the program for 3 weeks. They
also obtained serum from people who had followed the Pritikin
Program for a number of years. To clarify, the Pritikin Program
The exception is fish oil capsules, which will not have a negative
impact on insulin sensitivity. This diet is low in total fats
(under 15% of calories) and moderate in protein. Bean and soy
consumption should be moderate as well. Since high-glycemicindex carbohydrates can markedly boost post-meal insulin levels,
it may be advisable to emphasize whole-food carbohydrate
sources that are relatively low in glycemic index. This includes
pastas, most whole fruits, and whole-grain products that are
relatively structurally intact. For example, sprouted wheat breads
as compared to wheat flour breads.
This dietary program should be complemented by regular
aerobic exercise. Exercise where the patient supports his/her own
weight, such as brisk walking, stair-climbing, elliptical gliders, or
treadmills, is preferable. For patients less than ideally thin, Oasis
of Hope has a very effective regimen for fat loss. The Oasis of
Hope Leanness Program is based on a mini-fast with exercise
strategy developed by Austrian physician Dr. Babak Bahadori 24.
When volunteers from the hospital staff tried this program on
themselves, the participants on average lost one-quarter of their
initial body fat. The best thing about this program is that it is
sustainable for life, and does not require calorie counting or carb
avoidance.
For patients that are unwilling to adopt a fully vegan diet,
a more modest benefit can result by adopting a Mediterranean
diet in conjunction with regular exercise. The Mediterranean
approach to eating discourages the consumption of red meat and
fatty dairy products, allows moderate amounts of lean white meat
or fish, and emphasizes large intakes of fruits, vegetables (often
sauted in olive oil), beans, and whole grains. This approach
tends to improve insulin sensitivity because it minimizes intakes
of saturated fat while often increasing those of unsaturated fat. A
low ratio of saturated to unsaturated fats tends to improve insulin
sensitivity 25.
15
Emotional Support at Oasis of Hope
What if a person facing cancer was forced to decide
between being cared for by a doctor or a counselor? Whom
would he/she choose? Most people recognize that speaking with
a counselor would be helpful - but not at the cost of not being
able to see their doctor. A person might be thought crazy if they
chose to see a psychologist instead of the oncologist. In most
hospitals, patients do not encounter this dilemma. The choice has
already been made. It is rare to find counseling provided in cancer
treatment centers. At best, there may be a social worker who
comes for a quick interview. Notes are entered into the medical
file and that is it. Two years ago, the Oasis of Hope director of
counseling attended the annual convention of the Association of
Oncology Social Workers. The director came back very excited
about working at Oasis of Hope, explaining during breaks at the
conference, other social workers would ask about the program at
Oasis of Hope. They all were amazed that Oasis of Hope truly
integrates emotional support into its treatment program, and they
stated that they could only dream of working in such a place. In
most cancer treatment centers, emotional support is a nice thought
that happens minimally if at all.
This is not the case at Oasis of Hope. Counseling is
an integral part of the treatment program. Why? Cancer, its
symptoms, and treatments, will tax the strongest of people.
Fear, anxiety, anger and other strong emotions are promoted by
cancer, and few people have had to deal with such a difficult
situation that stresses them in so many different ways at the same
time. The whole experience can affect a persons sense of self,
Furthermore, chronic stress affects the body negatively in
several other ways. Through imbalance of the autonomic nervous
system, it affects the rhythm of the beats of the heart, and may
Grief is a normal part of experiencing a diagnosis of
cancer and the ensuing treatment. Few people realized how
many feelings of loss a patient goes through. The seeming loss
of hopes and dreams for the future can bring on grief. The loss
of a normal routine can feel devastating. A person should not go
through this process alone.
Feelings of loss are normally followed by the fifth stage,
which is anger. Think of a child who has his toy snatched away
from him by a bully. At first, he doesnt know what happened.
Then, he cant believe it. His fear of the bully is paralyzing and
then he starts to cry. After a time of crying, he gets angry. It is
common for a patient to express anger and frustration.
Anger is followed by a stage of guilt. Questions of Why
me? and What did I do to deserve this? are common. With the
help of Oasis of Hope counselors, the feelings of anger and grief
can be transformed into the seventh stage, which is acceptance
and resolve. When a patient is able to accept the situation, she
is emotionally ready to hope and believe that healing is possible,
and then she can find the courage to take action, knowing all the
time that the treatment outcome may not be what is desired.
Sarah Mahoney authored a great guideline for what to
do when diagnosed with cancer entitled This is Your Brain On
Illness 10. In her article, Mahoney acknowledges the emotional
stages that a cancer patient experiences, and she specifies actions
that can be taken to manage the stress and make effective
treatment decisions. Her main points are: 1) The first 5 minutes:
Youre in shock, just take it all in; 2) The first 24 hours: You seize
control. Dont commit to treatment yet; 3) The first week: You hit
a slump; 4) Identify your feelings; 5) Recruit your A team; 6)
Investigate self-management programs; 7) Embrace your inner
grouch; 8) Resist redefining yourself.
There is a close link between the experience of mind
and the physiological performance of the body 11. The body is
If a shift from a perception that a person is dying from
cancer can be made toward a renewed sense that a person is
dealing with cancer, much of the emotional distress and burdens
are alleviated. People need permission to engage in life and
enjoy each day whether cancer is present or not. The essence of
the Oasis of Hope emotional support program is just that. It is an
invitation to live each day to the fullest.
16
Caring for the Spirit at Oasis of Hope
Patients at Oasis of Hope in the 1960s through the early
2000s, would daily witness a kind old gentleman in a doctors
coat getting out of his burgundy Mercury Grand Marquis and
pulling out his briefcase and guitar case from the trunk. As aged
and frail as he was, his heart-felt smile and greeting brought
strength to anyone who was so fortunate to have met him. Dr.
Ernesto Contreras, Sr., founder of the Oasis of Hope, had been
providing his unique blend of scientific medicine and healing art
to the patients at the hospital for more than 35 years.
Dr. Contreras, Sr. would see patients in his consultation
office in the mornings to go over lab work and explain medical
treatments. In the afternoons, he would get together with all of
his patients for fellowship. He would take his guitar and a joke
book. Often his jokes were stale but he would laugh so hard
and sincerely that everyone would join in the fun. When it came
time to sing, he would pull out his songbook. When he realized
he couldnt read the small type, he would borrow glasses from
the person closest to him. Often, a woman named Peggy would
lend her oversized pink framed glasses to Dr. Contreras. He may
not have sung like Elton John, but some of the glasses he would
borrow could have come right out of Sir Elton Johns private
collection.
He loved to share incredible facts such as ironic doctors
names he came across including the pediatrician named Dr. Kidd,
the radiotherapist named Dr. Burns, and the cardiologist named
Dr. Hart. What was remarkable was to see smiles come across the
faces of many people in the room who were facing the difficult
reality of cancer.
Many of his songs were comical as well. He would take
lyrics penned by his patients and sing them to the tune of popular
folk songs. Imagine singing to the tune of Deep In The Heart
of Texas words like, The Contreras diet, you better best try it
(clap, clap, clap, clap), deep in the heart of Oasis. The enzymes
too, you need a few (clap, clap, clap, clap), deep in the heart of
Oasis. As he would have his patients sing along with him, more
smiles would brighten and an occasional tear of relief would be
shed. When a patient was discharged, Dr. Contreras would sing
his Farewell song to send him off with a blessing and love until
the next time they would meet.
After jokes and songs, he would ask everyone to form a
circle, hold hands and pray. He would pray in a very low and
humble voice. He had a simple faith that was contagious. To
close, he would prescribe 12 hugs and more tears of relief and joy
would often come to the eyes of many.
This story is more than heartwarming; it is fundamental
for the treatment approach at Oasis of Hope. Though there were
no published clinical trials on the healing importance of a patients
spirituality when Dr. Contreras, Sr. opened Oasis of Hope in 1963,
intuitively, he knew that he must address the needs of the whole
personbody, mind and spirit. It was because of Dr. Contreras,
Sr.s vision of lifting a patients spirit that he would integrate
music, laughter, prayer and hugs into his medical program. This
integration of spiritual support continues to be a hallmark of the
Oasis of Hope total care approach - a 45 - year healing legacy.
As scientists, we do not fully understand how the
spirituality of a patient impacts his or her health. A number of
clinical studies are beginning to skim the surface of this intriguing
subject.
One explanation of how the spirit of a person can impact his/
her physical health could include the linear relationship between
the spirit, mind and body. If there were one word to sum up this
linear relationship, it would be psychoneuroendocrinology.
Imagine that a person receives a diagnosis of cancer. This
person may be riddled with fear and anxiety related to death,
symptoms, and treatment. If the patient had faith that God was
going to help, no matter what the outcome would be, this faith
would generate positive emotions of peace and maybe even joy.
When these emotions were transferred from the soul of the person
to the brain, the brain would send signals to the endocrine system
that would then produce chemicals that could bring relief from
pain and a sense of well-being to the patient.
Another patient with no faith may feel hopeless. This
would generate negative emotions that would arrive to the
brain. When distress signals are received by the brain, orders are
fired out to the endocrine system to produce chemicals such as
adrenaline and cortisol to help the patient fight or flee from the
perceived danger. These chemicals are helpful in short bursts
but when a patient is distressed over a long period of time, the
chemicals begin to depress the immune system. A depressed
immune system will not help a patient heal.
The interconnection of a persons body, mind and spirit
is really not linear at all. It is more like overlapping circles. But
it is easy to see how the spirit can affect the emotions that in
turn stimulate a physiological response. There are many studies
that confirm that a patients spirituality can ease psychological
stress. Patients report that spirituality is an excellent way of
coping 1. Patients have indicated that sharing prayer and religious
expression has been effective at lowering emotional distress even
when it is done through online chat rooms 2.
Because Oasis of Hope goes beyond cancer eradication to
concentrate on the quality of life the patient experiences, spiritual
support is emphasized. Clinical studies confirm that religious
coping has a positive impact and improves the quality of life in
cancer patients 3.
In one study with 27 breast cancer patients, 26 out of the
27 stated that spiritual faith could help cancer patients recuperate,
citing prayer, dependence on God, and social support from the
faith community as being effective 4. Another study with 84
patients concluded that helping a patient find meaning in life
through spirituality had a positive impact on a patients ability to
manage the emotional strain of cancer 5.
Whether a person professes a belief in God or not, everyone
has spiritual needs. In cancer patients, some of the top spiritual
needs include: time to think; hope; dealing with unresolved
issues; preparation for death; expression of true feelings without
being judged; and the opportunity to speak about important
relationships 6. Such needs should not be overlooked. In most
hospitals, a visit by a chaplain may happen or it may not. Some
families may call a local pastor to come and visit. Usually a time
of sharing followed by prayer will happen in these cases and the
patient and family members often feel supported. At Oasis of
Hope, spiritual support is not an optional accessory. Spiritual
health and needs are acknowledged and addressed to the extent
that a patient is open to the opportunities from devotions, praise
and worship, and prayer times.
Clinical trials confirm the importance of faith, prayer,
religious expression, and shared faith. Dr. Contreras, Sr.
envisioned an Oasis of Hope with spiritual healing. Today, the
spiritual support program thrives as patients become active parts
in their healing and the healing of others.
A missionary who provides spiritual counseling at Oasis
of Hope recounts some of his experiences:
This is a story of a woman that came to Oasis of Hope as a
patient. Even before she came she recognized that she had a need
to get rid of any baggage that she might have from her past in
order for a complete healing. After a few days at Oasis of Hope,
during one of the morning devotions, she burst out and talked
about the hurts of her past and how they had affected her whole
life and she did not know how to forgive. Our Spiritual Support
Team came together and talked with her and offered comfort and
prayer. It was during that time that she was able to release those
hurts and feel Gods love for her in a tangible way. A year later
she still attributes her healing to this moment knowing that what
she would do medically would work because she had laid down
that burden.
This other story tells us about a patient who came through
the Oasis of Hope Program for three consecutive treatments. At
the end of her treatment she was given a report of being cancer
free. A report that many people hope to hear. She broke down
crying and came to the spiritual team one day. She couldnt be
happy about her good report. She was sure the cancer would
come back if she did not change how she felt about her husband.
Our team prayed with her, so that she would let go of the things
of the past.
17
Oasis of Hope IRT Survival Statistics
Though the scientific basis for the IRT protocols have
been substantiated in this book, for many, it all comes down to
survival statistics. Recently, we analyzed the survival of the first
group of patients who have been treated with our relatively new
IRT-Q and IRT-C protocols. Because these protocols have been
in place for only several years, we obviously have not been able to
calculate 5-year survivals yet, but we have been able to determine
meaningful 1- and 2-year survivals for the most common types
of cancer treated with the IRT-Q protocol. For the current IRT-C
protocol, which has now been in use for a little under 2 years,
we have had enough experience to calculate 1-year survivals in
breast, lung, and colorectal cancer. Since most patients who come
to Oasis of Hope have advanced metastatic disease when they get
here, we have restricted this analysis to patients who were stage
4 at the time of diagnosis, so that our results can be compared
objectively with those of other medical centers. Stage 4 usually
means that metastases are present in distant organs. Also, we
have included only those patients who were sufficiently healthy to
complete at least 3 courses of therapy, which usually takes about
3 months. In patients diagnosed with stage 4 breast cancer, we
have also done a separate analysis for those patients who arrived
at Oasis of Hope within 6 months of their diagnosis. For many
of these patients, Oasis of Hope was their first treatment option.
Tables I and II display our results. The results of
conventional treatment which we have included for comparison
are derived from the National Cancer Institutes recent (2007)
Oasis IRT-Q
Conventional Treatment *
1-Year
Survival (%)
2-Year
Survival (%)
1-Year
Survival (%)
2-Year
Survival (%)
Breast
92
68.2
65
44
Breast**
100
88.3
65
44
Lung
80.9
43.8
20
Ovarian
95
76.4
62
43
Colorectal
63
42.3
43
29
It is clear that, in terms of survival, Oasis of Hope patients
are doing better than those receiving the average standard of care
in the U.S. In particular, survival in lung cancer is strikingly better.
We are not doing as well with colorectal cancer. This cancer is
typically resistant to available chemotherapies. But, even here
our results appear to be superior to conventional treatment. Note
also that our results with stage 4 breast cancer patients who came
to Oasis soon after diagnosis are quite good a doubling of twoyear survival relative to conventional therapy.
With respect to the admittedly preliminary results of the
IRT-C protocol, it is encouraging that, even without chemotherapy
treatments, our patients have been doing better than those on
conventional therapy.
Admittedly, we cant claim that many of these patients
have been cured in the sense that the cancer has been
eliminated and wont come back. But it does seem that we are
making some progress toward the goal of turning advanced
cancer into a chronic disease that can be managed in the long
term rather like diabetes as opposed to a rapid death sentence.
And remember that our IRT protocols are in a constant state of
evolution barely a month goes by that we dont add some new
element to our regimens, or modify them in a way that seems
likely to improve their efficacy. So we are cautiously optimistic
that we are on the right track, and that our results will continue to
improve over the coming years.
Table II. Survival Rates for Stage IV Cancer IRT-C
Type of
Cancer
Oasis IRT-C
Conventional
Treatment*
1-Year
Survival (%)
1-Year
Survival (%)
Breast
74.4
65
Breast**
86.7
65
69
20
76.4
43
Lung
Colorectal
These results are promising and suggest that Oasis of
Hope should continue to evaluate new therapies and find ways
to integrate new proven modalities into a comprehensive cancer
management program that can improve the prognosis of a patient,
his quality of life, and his ability to engage in normal activities.
This is the commitment of the members of the Oasis of Hope
Health Group.
Epilogue
Uncertainty complicates any and all endeavors; acquiesce
to it, and failure is assured. The innumerable variables cancer
poses makes it a formidable foe. Those that remain static in their
quest to conquer it are doomed, be they researchers, oncologists,
or patients. Every advance in the knowledge of cancers intricate
biology brings along a new set of uncertainties; but new
opportunities also arise.
No one can deny the success that basic research has
brought about in the last three decades. Billions of dollars have
been granted to hundreds of thousands of scientists who have
gained fame in the prestigious world of cancer research, over
1.5 million scientific publications attest to their relentless work
worldwide.
It is largely due to the constant stream of new information
coming from this research that has made it possible for the Oasis
of Hope Clinical Research Organization to develop and improve
its Integrative Regulatory Therapies. Whether some of the
research of the various institutes and companies has been profit
driven or not, the reality is that we are able to take much of this
information and provide benefit to our patients.
Im proud of the percentage of patients we have been
able to help survive cancer in the history of our institution. As
we advance and modify our therapies, many have advised that I
should not change our proven approach. But the patients that
we could not help are a constant reminder that the good is the
enemy of the excellent. Not everything that is new is better and
not everything that is old is outdated. A balance of the innovative
with the time-tested is the premise of our forward approach to a
dynamic development of new therapies.
In the ideal world, researchers, clinicians, and investors
should be working together to develop therapies that are successful,
well tolerated by the patients, easy to apply, and affordable.
Though this point of view may categorize me as an idealist, I
persist in the quest to develop effective and efficient therapies.
Im proud, blessed, and extremely grateful for the enormously
talented team that has joined the Oasis of Hope to envision and
seek the impossible dream of alleviating the world of cancer.
Francisco Contreras, MD
Chairman & President
Oasis of Hope Health Group
References
Chapter Five- Oxidizing Cancer to Death
1. Sun Y. Free radicals, antioxidant enzymes, and carcinogenesis. Free Radic Biol Med
1990;8(6):583-99.
2. Kwei KA, Finch JS, Thompson EJ, Bowden GT. Transcriptional repression of
catalase in mouse skin tumor progression. Neoplasia 2004 September;6(5):440-8.
3. Tas F, Hansel H, Belce A, Ilvan S, Argon A, Camlica H, Topuz E. Oxidative stress in
breast cancer. Med Oncol 2005;22(1):11-5.
4. Arnold RS, Shi J, Murad E, Whalen AM, Sun CQ, Polavarapu R, Parthasarathy
S, Petros JA, Lambeth JD. Hydrogen peroxide mediates the cell growth and
transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci USA 2001
May 8;98(10):5550-5.
5. Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS. Reactive
oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer
cells. J Biol Chem2004August.13;279(33):34643-54.
6. Lim SD, Sun C, Lambeth JD, Marshall F, Amin M, Chung L, Petros JA, Arnold
RS. Increased Nox1 and hydrogen peroxide in prostate cancer. Prostate 2005 February
1;62(2):200-7.
7. Arnold RS, Shi J, Murad E, Whalen AM, Sun CQ, Polavarapu R, Parthasarathy
S, Petros JA, Lambeth JD. Hydrogen peroxide mediates the cell growth and
transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci USA 2001
May 8;98(10):5550-5.
8. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E,
Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells:
action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA
2005September20;102(38):13604-9.
9. Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput
C, Kirk KL, Buettner GR, Levine M. Ascorbate in pharmacologic concentrations
selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in
vivo. Proc Natl Acad Sci USA 2007 May 22;104(21):8749-54.
10. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine
M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern
Med 2004,April6;140(7):533-7.
11. Padayatty SJ, Levine M. Reevaluation of ascorbate in cancer treatment: emerging
evidence, open minds and serendipity. J Am Coll Nutr 2000 August;19(4):423-5.
12. Riordan HD, Casciari JJ, Gonzalez MJ, Riordan NH, Miranda-Massari JR, Taylor
P, Jackson JA. A pilot clinical study of continuous intravenous ascorbate in terminal
cancer patients. P R Health Sci J 2005 December;24(4):269-76.
13. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously
administered vitamin C as cancer therapy: three cases. CMAJ 2006 March
28;174(7):937-42.
14. Calderon PB, Cadrobbi J, Marques C, Hong-Ngoc N, Jamison JM, Gilloteaux J,
Summers JL, Taper HS. Potential therapeutic application of the association of vitamins
C and K3 in cancer treatment. Curr Med Chem 2002 December;9(24):2271-85.
15. Sharma RK, Marwaha N, Kumar P, Narang A. Effect of oral water soluble vitamin
K on PIVKA-II levels in newborns. Indian Pediatr 1995 August;32(8):863-7.
16. Venugopal M, Jamison JM, Gilloteaux J, Koch JA, Summers M, Giammar D,
Sowick C, Summers JL. Synergistic antitumor activity of vitamins C and K3 on human
urologic tumor cell lines. Life Sci 1996;59 (17):1389-400.
|
17. Gilloteaux J, Jamison JM, Neal DR, Summers JL. Cell death by autoschizis in
TRAMP prostate carcinoma cells as a result of treatment by ascorbate: menadione
combination.UltrastructPathol2005 May;29(3-4):221-35.
18. Zhang W, Negoro T, Satoh K, Jiang Y, Hashimoto K, Kikuchi H, Nishikawa H,
Miyata T, Yamamoto Y, Nakano K, Yasumoto E, Nakayachi T, Mineno K, Satoh T,
Sakagami H. Synergistic cytotoxic action of vitamin C and vitamin K3. Anticancer Res
2001 September; 21(5):3439-44.
19. Verrax J, Cadrobbi J, Delvaux M, Jamison JM, Gilloteaux J, Summers JL, Taper HS,
Buc CP. The association of vitamins C and K3 kills cancer cells mainly by autoschizis,
a novel form of cell death. Basis for their potential use as coadjuvants in anticancer
therapy. Eur J Med Chem2003May;38(5):451-7.
20. Gilloteaux J, Jamison JM, Arnold D, Neal DR, Summers JL. Morphology and DNA
degeneration during autoschizic cell death in bladder carcinoma T24 cells induced
by ascorbate and menadione treatment. Anat Rec A Discov Mol Cell Evol Biol 2006
January;
43. Whittle BJ, Hansen D, Salmon JA. Gastric ulcer formation and cyclo-oxygenase
inhibition in cat antrum follows parenteral administration of aspirin but not salicylate.
Eur J Pharmacol 1985 October 8;116(1-2):153-7.
44. Zambraski EJ, Atkinson DC, Diamond J. Effects of salicylate vs. aspirin on renal
prostaglandins and function in normal and sodium-depleted dogs. J Pharmacol Exp
Ther 1988 Oct;247(1):96-103.
45. Boettcher FA, Salvi RJ. Salicylate ototoxicity: review and synthesis. Am J
Otolaryngol 1991 January;12(1):33-47.
46. McPherson TC. Salsalate for arthritis: a clinical evaluation. Clin Ther
1984;6(4):388-403.
47. Singh RP, Mallikarjuna GU, Sharma G, Dhanalakshmi S, Tyagi AK, Chan DC,
Agarwal C, Agarwal R. Oral silibinin inhibits lung tumor growth in athymic nude
mice and forms a novel chemocombination with doxorubicin targeting nuclear factor
kappaB-mediated inducible chemoresistance. Clin Cancer Res 2004 December
15;10(24):8641-7.
48. Flaig TW, Su LJ, Harrison G, Agarwal R, Glode LM. Silibinin synergizes with
mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer
cells. Int J Cancer 2007 May 1;120(9):2028-33.
49. Fakih M, Cao S, Durrani FA, Rustum YM. Selenium protects against toxicity
induced by anticancer drugs and augments antitumor activity: a highly selective, new,
and novel approach for the treatment of solid tumors. Clin Colorectal Cancer 2005
July;5(2):132-5.
50. Beer TM, Myrthue A. Calcitriol in cancer treatment: from the lab to the clinic. Mol
Cancer Ther 2004 March;3(3):373-81.
51. Weitsman GE, Koren R, Zuck E, Rotem C, Liberman UA, Ravid A. Vitamin D
sensitizes breast cancer cells to the action of H2O2: mitochondria as a convergence
point in the death pathway. Free Radic Biol Med 2005 July 15;39(2):266-78.
52. Koren R, Hadari-Naor I, Zuck E, Rotem C, Liberman UA, Ravid A. Vitamin D is a
prooxidant in breast cancer cells. Cancer Res 2001 February 15;61(4):1439-44.
18. Eisinger AL, Prescott SM, Jones DA, Stafforini DM. The role of cyclooxygenase-2 and
prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat 2007;82:147-54.
19. Liao Z, Mason KA, Milas L. Cyclo-oxygenase-2 and its inhibition in cancer : is
there a role? Drugs 2007;67:821-45.
20. Zeddou M, Greimers R, de Valensart N, Nayjib B, Tasken K, Boniver J et al.
Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A
receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type
I pathway. Biochem Pharmacol 2005;70:714-24.
21. Klein S, de Fougerolles AR, Blaikie P, Khan L, Pepe A, Green CD et al. Alpha 5 beta
1 integrin activates an NF-kappa B-dependent program of gene expression important
for angiogenesis and inflammation. Mol Cell Biol 2002;22:5912-22.
22. Gately S, Li WW. Multiple roles of COX-2 in tumor angiogenesis: a target for
antiangiogenic therapy. Semin Oncol 2004;31:2-11.
23. Williams CS, Tsujii M, Reese J, Dey SK, DuBois RN. Host cyclooxygenase-2
modulates carcinoma growth. J Clin Invest 2000;105:1589-94.
24. Tisdale MJ. Cancer cachexia. Langenbecks Arch Surg 2004;389:299-305.
25. Whittle BJ, Hansen D, Salmon JA. Gastric ulcer formation and cyclo-oxygenase
inhibition in cat antrum follows parenteral administration of aspirin but not salicylate.
Eur J Pharmacol 1985;116:153-57.
26. Zambraski EJ, Atkinson DC, Diamond J. Effects of salicylate vs. aspirin on renal
prostaglandins and function in normal and sodium-depleted dogs. J Pharmacol Exp
Ther 1988;247:96-103.
27. Cryer B, Goldschmiedt M, Redfern JS, Feldman M. Comparison of salsalate and
aspirin on mucosal injury and gastroduodenal mucosal prostaglandins. Gastroenterology
1990;99:1616-21.
28. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin.
Science 1994;265:956-59.
29. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and
salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998;396:77-80.
30. Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, Arthur HM.
Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis
through a Cox-independent mechanism. FASEB J 2006;20:2009-16.
3. Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res 2003;90:127-56.
4. Hallett WH, Murphy WJ. Natural killer cells: biology and clinical use in cancer
therapy. Cell Mol Immunol 2004;1:12-21.
5. Maestroni GJ, Conti A, Pierpaoli W. Pineal melatonin, its fundamental
immunoregulatory role in aging and cancer. Ann NY Acad Sci 1988;521:140-48.
6. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V et al. Regulation of
antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004;36:1-9.
7. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms
from radical detoxification to radical avoidance. Endocrine 2005;27:119-30.
8. Oz E, Ilhan MN. Effects of melatonin in reducing the toxic effects of doxorubicin.
Mol Cell Biochem 2006;286:11-15.
9. Kim C, Kim N, Joo H, Youm JB, Park WS, Cuong DV et al. Modulation by melatonin
of the cardiotoxic and antitumor activities of adriamycin. J Cardiovasc Pharmacol
2005;46:200-10.
10. Atessahin A, Sahna E, Turk G, Ceribasi AO, Yilmaz S, Yuce A et al. Chemoprotective
effect of melatonin against cisplatin-induced testicular toxicity in rats. J Pineal Res
2006;41:21-27.
11. Hara M, Yoshida M, Nishijima H, Yokosuka M, Iigo M, Ohtani-Kaneko R et al.
Melatonin, a pineal secretory product with antioxidant properties, protects against
cisplatin-induced nephrotoxicity in rats. J Pineal Res 2001;30:129-38.
12. Lissoni P, Paolorossi F, Ardizzoia A, Barni S, Chilelli M, Mancuso M et al. A
randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine
therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line
treatment of advanced non-small cell lung cancer patients in a poor clinical state. J
Pineal Res 1997;23:15-19.
13. Anwar MM, Mahfouz HA, Sayed AS. Potential protective effects of melatonin on
bone marrow of rats exposed to cytotoxic drugs. Comp Biochem Physiol A Mol Integr
Physiol 1998;119:493-501.
14. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized
study with the pineal hormone melatonin versus supportive care alone in patients with
brain metastases due to solid neoplasms. Cancer 1994;73:699-701.
27. Rose DP, Connolly JM. Regulation of tumor angiogenesis by dietary fatty acids and
eicosanoids. Nutr Cancer 2000;37:119-27.
28. Murota SI, Onodera M, Morita I. Regulation of angiogenesis by controlling VEGF
receptor. Ann NY Acad Sci 2000;902:208-12.
29. Shtivelband MI, Juneja HS, Lee S, Wu KK. Aspirin and salicylate inhibit colon
cancer medium- and VEGF-induced endothelial tube formation: correlation with
suppression of cyclooxygenase-2 expression. J Thromb Haemost 2003;1:2225-33.
30. Liao Z, Mason KA, Milas L. Cyclo-oxygenase-2 and its inhibition in cancer : is
there a role? Drugs 2007;67:821-45.
31. Claria J, Romano M. Pharmacological intervention of cyclooxygenase-2 and
5-lipoxygenase pathways. Impact on inflammation and cancer. Curr Pharm Des
2005;11:3431-47.
32. Tisdale MJ. Inhibition of lipolysis and muscle protein degradation by EPA in cancer
cachexia. Nutrition 1996;12:S31-S33.
33. Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of
skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer
Res 2001;61:3604-09.
34. Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral
eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer
2000;36:177-84.
35. Fearon KC, von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ
et al. Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on
loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut
2003;52:1479-86.
36. Pardini RS. Nutritional intervention with omega-3 fatty acids enhances tumor
response to anti-neoplastic agents. Chem Biol Interact 2006;162:89-105.
37. Colas S, Paon L, Denis F, Prat M, Louisot P, Hoinard C et al. Enhanced
radiosensitivity of rat autochthonous mammary tumors by dietary docosahexaenoic
acid. Int J Cancer 2004;109:449-54.
38. Townsend K, Banwell CM, Guy M, Colston KW, Mansi JL, Stewart PM et al.
Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer
Res 2005;11:3579-86.
39. Townsend K, Evans KN, Campbell MJ, Colston KW, Adams JS, Hewison M.
Biological actions of extra-renal 25-hydroxyvitamin D-1alpha-hydroxylase and
implications for chemoprevention and treatment. J Steroid Biochem Mol Biol
2005;97:103-09.
40. Banerjee P, Chatterjee M. Antiproliferative role of vitamin D and its analogs--a
brief overview. Mol Cell Biochem 2003;253:247-54.
41. Holick MF. Environmental factors that influence the cutaneous production of
vitamin D. Am J Clin Nutr JID - 0376027 1995;61:638S-45S.
42. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and
safety. Am J Clin Nutr JID - 0376027 1999;69:842-56.
43. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes,
heart disease, and osteoporosis. Am J Clin Nutr 2004;79:362-71.
44. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality:
a review (United States). Cancer Causes Control 2005;16:83-95.
45. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB et al. The
role of vitamin D in cancer prevention. Am J Public Health 2006;96:252-61.
46. Krause R, Matulla-Nolte B, Essers M, Brown A, Hopfenmuller W. UV radiation
and cancer prevention: what is the evidence? Anticancer Res 2006;26:2723-27.
47. Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights. Curr.Opin.
Clin Nutr Metab Care 2007;10:6-11.
48. Grant WB, Garland CF, Gorham ED. An estimate of cancer mortality rate reductions
in Europe and the US with 1,000 IU of oral vitamin D per day. Recent Results Cancer
Res 2007;174:225-34.
49. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate
doses of solar ultraviolet-B radiation. Cancer 2002;94:1867-75.
50. Friedrich M, Rafi L, Mitschele T, Tilgen W, Schmidt W, Reichrath J. Analysis of
the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent
Results Cancer Res 2003;164:239-46.
51. Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced
by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma
and carcinoma cells: possible implications for prevention and therapy. Cancer Res
2000;60:2304-12.
63. Kang SN, Lee MH, Kim KM, Cho D, Kim TS. Induction of human promyelocytic
leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein
kinase C. Biochem Pharmacol 2001;61:1487-95.
64. Sharma G, Singh RP, Chan DC, Agarwal R. Silibinin induces growth inhibition and
apoptotic cell death in human lung carcinoma cells. Anticancer Res 2003;23:2649-55.
65. Qi L, Singh RP, Lu Y, Agarwal R, Harrison GS, Franzusoff A et al. Epidermal
growth factor receptor mediates silibinin-induced cytotoxicity in a rat glioma cell line.
Cancer Biol Ther 2003;2:526-31.
66. Agarwal C, Singh RP, Dhanalakshmi S, Tyagi AK, Tecklenburg M, Sclafani RA
et al. Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and
causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene
2003;22:8271-82.
67. Tyagi AK, Agarwal C, Singh RP, Shroyer KR, Glode LM, Agarwal R. Silibinin
down-regulates survivin protein and mRNA expression and causes caspases activation
and apoptosis in human bladder transitional-cell papilloma RT4 cells. Biochem Biophys
Res Commun 2003;312:1178-84.
68. Varghese L, Agarwal C, Tyagi A, Singh RP, Agarwal R. Silibinin efficacy against
human hepatocellular carcinoma. Clin Cancer Res 2005;11:8441-48.
69. Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS. Silibinin suppresses PMAinduced MMP-9 expression by blocking the AP-1 activation via MAPK signaling
pathways in MCF-7 human breast carcinoma cells. Biochem.Biophys.Res.Commun
2007;354:165-71.
70. Tyagi AK, Agarwal C, Chan DC, Agarwal R. Synergistic anti-cancer effects of
silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin
against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep
2004;11:493-99.
71. Singh RP, Agarwal R. A cancer chemopreventive agent silibinin, targets mitogenic
and survival signaling in prostate cancer. Mutat Res 2004;555:21-32.
72. Hannay JA, Yu D. Silibinin: a thorny therapeutic for EGF-R expressing tumors?
Cancer Biol Ther 2003;2:532-33.
73. Singh RP, Dhanalakshmi S, Tyagi AK, Chan DC, Agarwal C, Agarwal R. Dietary
feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude
mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer
Res 2002;62:3063-69.
87. Fakih M, Cao S, Durrani FA, Rustum YM. Selenium protects against toxicity
induced by anticancer drugs and augments antitumor activity: a highly selective,
new, and novel approach for the treatment of solid tumors. Clin Colorectal Cancer
2005;5:132-35.
88. Shin SH, Yoon MJ, Kim M, Kim JI, Lee SJ, Lee YS et al. Enhanced lung cancer
cell killing by the combination of selenium and ionizing radiation. Oncol Rep
2007;17:209-16.
89. Fischer JL, Mihelc EM, Pollok KE, Smith ML. Chemotherapeutic selectivity
conferred by selenium: a role for p53-dependent DNA repair. Mol Cancer Ther
2007;6:355-61.
90. Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky G.
Supplementation with selenium and human immune cell functions. II. Effect on
cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 1994;41:115-27.
91.
Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky
G. Supplementation with selenium augments the functions of natural killer and
lymphokine-activated killer cells. Biol. Trace Elem Res 1996;52:227-39.
92. Cao Y, Cao R. Angiogenesis inhibited by drinking tea. Nature 1999;398:381.
93. Jung YD, Kim MS, Shin BA, Chay KO, Ahn BW, Liu W et al. EGCG, a major
component of green tea, inhibits tumour growth by inhibiting VEGF induction in
human colon carcinoma cells. Br J Cancer 2001;84:844-50.
94. Jung YD, Ellis LM. Inhibition of tumour invasion and angiogenesis by
epigallocatechin gallate (EGCG), a major component of green tea. Int J Exp Pathol
2001;82:309-16.
95. Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK et al.
Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol
2001;19:1830-38.
96. Lamy S, Gingras D, Beliveau R. Green tea catechins inhibit vascular endothelial
growth factor receptor phosphorylation. Cancer Res 2002;62:381-85.
97. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical
and clinical studies. Anticancer Res 2003;23:363-98.
98. Singh S, Khar A. Biological effects of curcumin and its role in cancer chemoprevention
and therapy. Anticancer Agents Med Chem 2006;6:259-70.
99. LoTempio MM, Veena MS, Steele HL, Ramamurthy B, Ramalingam TS, Cohen
AN et al. Curcumin suppresses growth of head and neck squamous cell carcinoma. Clin
Cancer Res 2005;11:6994-7002.
100. Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY. The effects of curcumin on the
invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic Dis
2006;9:147-52.
101.
Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin with and without
oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer.
Mol Cancer Ther 2007;6:1276-82.
102. Kawamori T, Lubet R, Steele VE, Kelloff GJ, Kaskey RB, Rao CV et al.
Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory
agent, during the promotion/progression stages of colon cancer. Cancer Res
1999;59:597-601.
103. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF.
Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and
CYP3A4. J Pharmacol Exp Ther 2002;302:645-50.
104. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of
piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta
Med 1998;64:353-56.
105. Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS. Piperine enhances the
bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J Nutr
2004;134:1948-52.
106. Singh RP, Tyagi AK, Dhanalakshmi S, Agarwal R, Agarwal C. Grape seed extract
inhibits advanced human prostate tumor growth and angiogenesis and upregulates
insulin-like growth factor binding protein-3. Int J Cancer 2004;108:733-40.
107. Kaur M, Singh RP, Gu M, Agarwal R, Agarwal C. Grape seed extract inhibits
in vitro and in vivo growth of human colorectal carcinoma cells. Clin Cancer Res
2006;12:6194-202.
108. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNFinduced activation of nuclear transcription factors NF-kappa B, activator protein-1,
and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J
Immunol 2000;164:6509-19.
109. Bogden JD. Influence of zinc on immunity in the elderly. J Nutr Health Aging
2004;8:48-54.
110. Ammon HP. Boswellic acids in chronic inflammatory diseases. Planta Med
2006;72:1100-16.
111. Safayhi H, Sailer ER, Ammon HP. Mechanism of 5-lipoxygenase inhibition by
acetyl-11-keto-beta-boswellic acid. Mol Pharmacol 1995;47:1212-16.
112. Ghosh J, Myers CE. Inhibition of arachidonate 5-lipoxygenase triggers massive
apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 1998;95:13182-87.
113. Ding XZ, Tong WG, Adrian TE. Multiple signal pathways are involved
in the mitogenic effect of 5(S)-HETE in human pancreatic cancer. Oncology
2003;65:285-94.
114. Ihara A, Wada K, Yoneda M, Fujisawa N, Takahashi H, Nakajima A. Blockade of
leukotriene B4 signaling pathway induces apoptosis and suppresses cell proliferation
in colon cancer. J Pharmacol Sci 2007;103:24-32.
115. Tong WG, Ding XZ, Witt RC, Adrian TE. Lipoxygenase inhibitors attenuate growth
of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial
pathway. Mol Cancer Ther 2002;1:929-35.
116.
Tsukada T, Nakashima K, Shirakawa S. Arachidonate 5-lipoxygenase
inhibitors show potent antiproliferative effects on human leukemia cell lines. Biochem.
Biophys Res Commun 1986;140:832-36.
117. Ghosh J, Myers CE. Arachidonic acid stimulates prostate cancer cell growth:
critical role of 5-lipoxygenase. Biochem.Biophys.Res Commun 1997;235:418-23.
118. Avis I, Hong SH, Martinez A, Moody T, Choi YH, Trepel J et al. Fivelipoxygenase inhibitors can mediate apoptosis in human breast cancer cell
lines through complex eicosanoid interactions. FASEB J 2001;15:2007-09.
119. Fan XM, Tu SP, Lam SK, Wang WP, Wu J, Wong WM et al. Five-lipoxygenaseactivating protein inhibitor MK-886 induces apoptosis in gastric cancer through
upregulation of p27kip1 and bax. J Gastroenterol Hepatol 2004;19:31-37.
120. Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S et al Increased
5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal
cancer: a potential target for prevention. Carcinogenesis 2005;26:785-91.
121. Matsuyama M, Yoshimura R, Mitsuhashi M, Tsuchida K, Takemoto Y, Kawahito
Y et al. 5-Lipoxygenase inhibitors attenuate growth of human renal cell carcinoma and
induce apoptosis through arachidonic acid pathway. Oncol Rep 2005;14:73-79.
122. Hayashi T, Nishiyama K, Shirahama T. Inhibition of 5-lipoxygenase pathway
suppresses the growth of bladder cancer cells. Int J Urol 2006;13:1086-91.
134. Amin K, Li J, Chao WR, Dewhirst MW, Haroon ZA. Dietary glycine
inhibits angiogenesis during wound healing and tumor growth. Cancer Biol Ther
2003;2:173-78.
135. McCarty MF. The anti-angiogencic impact of dietary of glycine may be mediated
by a hyperpolarization-induced suppression of NADPH oxidase activity. Medical
Hypotheses 2007;in press.
136. Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R et al.
Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of
modified citrus pectin. J Natl Cancer Inst 2002;94:1854-62.
137. Takenaka Y, Fukumori T, Raz A. Galectin-3 and metastasis. Glycoconj J
2004;19:543-49.
138. Inufusa H, Nakamura M, Adachi T, Aga M, Kurimoto M, Nakatani Y et al. Role of
galectin-3 in adenocarcinoma liver metastasis. Int J Oncol 2001;19:913-19.
139. Inohara H, Raz A. Effects of natural complex carbohydrate (citrus pectin) on murine
melanoma cell properties related to galectin-3 functions. Glycoconj J 1994;11:527-32.
140. Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ et al.
Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol
2000;156:899-909.
141. Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI. Modified
citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with
prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 2003;6:301-04.
142. Cao Y, Feng Z, Hoos A, Klimberg VS. Glutamine enhances gut glutathione
production. JPEN J Parenter Enteral Nut. 1998;22:224-27.
143. Yoshida S, Kaibara A, Ishibashi N, Shirouzu K. Glutamine supplementation in
cancer patients. Nutrition 2001;17:766-68.
144. Jensen JC, Schaefer R, Nwokedi E, Bevans DW, III, Baker ML, Pappas AA et
al. Prevention of chronic radiation enteropathy by dietary glutamine. Ann Surg Oncol
1994;1:157-63.
145. Klimberg VS, Souba WW, Dolson DJ, Salloum RM, Hautamaki RD, Plumley
DA et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury.
Cancer 1990;66:62-68.
Biotin
enhances
guanylate
cyclase
activity.
Science
12. Chen X, Anderson JJ. Isoflavones inhibit proliferation of ovarian cancer cells in
vitro via an estrogen receptor-dependent pathway. Nutr Cancer 2001;41:165-71.
13. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J,
Rodabough RJ et al. Estrogen plus progestin and colorectal cancer in postmenopausal
women. N Engl J Med 2004;350:991-1004.
14. Kurahashi N, Iwasaki M, Sasazuki S, Otani T, Inoue M, Tsugane S. Soy product
and isoflavone consumption in relation to prostate cancer in Japanese men. Cancer
Epidemiol. Biomarkers Prev 2007;16:538-45.
15. Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P. Dietary
phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr
2006;136:3046-53.
16. Zhang M, Xie X, Lee AH, Binns CW. Soy and isoflavone intake are associated with
reduced risk of ovarian cancer in southeast china. Nutr Cancer 2004;49:125-30.
17. Hikosaka A, Asamoto M, Hokaiwado N, Kato K, Kuzutani K, Kohri K et al.
Inhibitory effects of soy isoflavones on rat prostate carcinogenesis induced by 2-amino1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 2004;25:381-87.
18. Guo JY, Li X, Browning JD, Jr., Rottinghaus GE, Lubahn DB, Constantinou A et al.
Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type
mice from carcinogen-induced colon cancer. J Nutr 2004;134:179-82.
19. Tanaka T, Kohno H, Tanino M, Yanaida Y. Inhibitory effects of estrogenic
compounds, 4-nonylphenol and genistein, on 7,12-dimethylbenz[a]anthracene-induced
ovarian carcinogenesis in rats. Ecotoxicol Environ Saf 2002;52:38-45.
20. Raffoul JJ, Banerjee S, Singh-Gupta V, Knoll ZE, Fite A, Zhang H et al. Downregulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy
isoflavones enhances prostate cancer radiotherapy in vitro and in vivo. Cancer Res
2007;67:2141-49.
21. Maskarinec G, Morimoto Y, Hebshi S, Sharma S, Franke AA, Stanczyk FZ. Serum
prostate-specific antigen but not testosterone levels decrease in a randomized soy
intervention among men. Eur J Clin Nutr 2006;60:1423-29.
22. Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and
prostate cancer. Exp Biol Med (Maywood) 2002;227:852-59.
23. Tang L, Jin T, Zeng X, Wang JS. Lycopene inhibits the growth of human
androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr
2005;135:287-90.
24. Ansari MS, Gupta NP. Lycopene: a novel drug therapy in hormone refractory
metastatic prostate cancer. Urol Oncol 2004;22:415-20.
25. Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy
alone in the management of advanced prostate cancer. BJU Int 2003;92:375-78.
26. Schroder FH, Roobol MJ, Boeve ER, de Mutsert R, Zuijdgeest-van Leeuwen SD,
Kersten I et al. Randomized, double-blind, placebo-controlled crossover study in men
with prostate cancer and rising PSA: effectiveness of a dietary supplement. Eur Urol
2005;48:922-30.
27. Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, van Breemen
R et al. Oxidative DNA damage in prostate cancer patients consuming tomato saucebased entrees as a whole-food intervention. J NatlCancer Inst 2001;93:1872-79.
28. Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A et al.
Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion
of human prostate cancer cells. J Med Food 2004;7:274-83.
29. Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. Pomegranate fruit
juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci
USA 2005;102:14813-18.
30. Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ et al. Phase
II study of pomegranate juice for men with rising prostate-specific antigen following
surgery or radiation for prostate cancer. Clin Cancer Res 2006;12:4018-26.
31. Khan N, Hadi N, Afaq F, Syed DN, Kweon MH, Mukhtar H. Pomegranate fruit
extract inhibits prosurvival pathways in human A549 lung carcinoma cells and tumor
growth in athymic nude mice. Carcinogenesis 2007;28:163-73.
32. Khan N, Afaq F, Kweon MH, Kim K, Mukhtar H. Oral consumption of pomegranate
fruit extract inhibits growth and progression of primary lung tumors in mice. Cancer
Res 2007;67:3475-82.
33. Casey AC, Bliznakov EG. Effect and structure-activity relationship of the coenzymes
Q on the phagocytic rate of rats. Chem Biol Interact 1972;5:1-12.
34. Bliznakov E, Casey A, Premuzic E. Coenzymes Q: stimulants of the phagocytic
activity in rats and immune response in mice. Experientia 1970;26:953-54.
35. Lockwood K, Moesgaard S, Folkers K. Partial and complete regression of breast
cancer in patients in relation to dosage of coenzyme Q10. Biochem Biophys Res
Commun 1994;199:1504-08.
8. Primrose JN, Miller GV, Preston SR, Gokhale J, Ambrose NS, Ward UM, Mills
JG, Ehsanullah RS, Darekar B. A prospective randomised controlled study of the use
of ranitidine in patients with gastric cancer. Yorkshire GI Tumour Group. Gut 1998
January;42(1):17-9.
9. Nielsen HJ, Christensen IJ, Moesgaard F, Kehlet H. Ranitidine as adjuvant treatment
in colorectal cancer. Br J Surg 2002 November;89(11):1416-22.
10 Kobayashi K, Matsumoto S, Morishima T, Kawabe T, Okamoto T. Cimetidine
inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking
E-selectin expression. Cancer Res 2000 July 15;60(14):3978-84.
11. Kannagi R, Izawa M, Koike T, Miyazaki K, Kimura N. Carbohydrate-mediated cell
adhesion in cancer metastasis and angiogenesis. Cancer Sci 2004 May;95(5):377-84.
12. Adams WJ, Morris DL. Short-course cimetidine and survival with colorectal cancer.
Lancet 1994 December 24;344(8939-8940):1768-9.
13. Natori T, Sata M, Nagari R, Makuuchi M. Cimetidine inhibits angiogenesis and
suppresses tumor growth. Biomed Pharmacother 2005 January;59(1-2):56-60.
14. Aoki M, Kanamori M, Yudoh K, Ohmori K, Yasuda T, Kimura T. Effects of vascular
endothelial growth factor and E-selectin on angiogenesis in the murine metastatic RCT
sarcoma. Tumour Biol 2001 July;22(4):239-46.
15. Garcia Rodriguez LA, Jick H. Risk of gynaecomastia associated with cimetidine,
omeprazole, and other antiulcer drugs. BMJ 1994 February 19;308(6927):503-6.
15. Marks PA, Dokmanovic M. Histone deacetylase inhibitors: discovery and
development as anticancer agents. Expert Opin Investig Drugs 2005;14:1497-511.
17. Liu T, Kuljaca S, Tee A, Marshall GM. Histone deacetylase inhibitors:
multifunctional anticancer agents. Cancer Treat Rev 2006;32:157-65.
18. Zhang X, Yashiro M, Ren J, Hirakawa K. Histone deacetylase inhibitor, trichostatin
A, increases the chemosensitivity of anticancer drugs in gastric cancer cell lines. Oncol
Rep 2006;16:563-68.
19. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F. Inhibition of
histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer
Res 2003;63:7291-300.
20. Zhang Y, Jung M, Dritschilo A, Jung M. Enhancement of radiation sensitivity
of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat Res
2004;161:667-74.