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Cancer Drugs 1st Edition Judy Matray-Devoti Digital
Instant Download
Author(s): Judy Matray-devoti
ISBN(s): 9780791085547, 0791085546
Edition: 1
File Details: PDF, 4.09 MB
Year: 2007
Language: english
DRUGS
The Straight Facts
Cancer Drugs
DRUGS The Straight Facts
Alcohol
Alzheimer’s Disease and Memory Drugs
Anti-Anxiety Drugs
Antidepressants
Barbiturates
Birth Control Pills
Body Enhancement Products
Cancer Drugs
Cocaine
Codeine
Date Rape Drugs
Designer Drugs
Diet Pills
Ecstasy
Hallucinogens
Heroin
Inhalants
Marijuana
Morphine
Nicotine
Opium
Peyote and Mescaline
Prescription Pain Relievers
Ritalin and Other Methylphenidate-Containing Drugs
Sleep Aids
DRUGS
The Straight Facts
Cancer Drugs
Judith Matray-Devoti, R.Ph., Ph.D
Consulting Editor
David J. Triggle
University Professor
School of Pharmacy and Pharmaceutical Sciences
State University of New York at Buffalo
Cancer Drugs
Copyright © 2006 by Infobase Publishing
All rights reserved. No part of this book may be reproduced or utilized in any
form or by any means, electronic or mechanical, including photocopying,
recording, or by any information storage or retrieval systems, without permission
in writing from the publisher. For information contact:
Chelsea House
An imprint of Infobase Publishing
132 West 31st Street
New York NY 10001
Library of Congress Cataloging-in-Publication Data
Maltray-Devoti, Judith.
Cancer drugs / Judith Matray-Devoti.
p. cm. — (Drugs : the straight facts)
Includes bibliographical references and index.
ISBN 0-7910-8554-6 (hardcover)
1. Cancer—Chemotherapy—Juvenile literature. 2. Antineoplastic
agents—Juvenile literature. I. Title. II. Series.
RC271. C5M17 2006
616.99’4061—dc 22 2006020616
Chelsea House books are available at special discounts when purchased in bulk
quantities for businesses, associations, institutions, or sales promotions. Please call our
Special Sales Department in New York at (212) 967-8800 or (800) 322-8755.
You can find Chelsea House on the World Wide Web at http://www.chelseahouse.com
Text and cover design by Terry Mallon
Printed in the United States of America
Bang EJB 10 9 8 7 6 5 4 3 2 1
This book is printed on acid-free paper.
All links and web addresses were checked and verified to be correct at the time
of publication. Because of the dynamic nature of the web, some addresses and
links may have changed since publication and may no longer be valid.
Table of Contents
Drugs and Their Uses
David J. Triggle, Ph.D. 6
Introduction 9
1. The Cellular Basis of Cancer 10
2. Alkylating Agents 22
3. Antimetabolites 38
4. Natural Products 48
5. Hormones and Hormone Antagonists 64
6. Molecularly Targeted Agents 78
7. Biologic Response Modifiers 94
8. Miscellaneous Agents 99
9. The Future 113
Glossary 117
Bibliography 123
Further Reading 125
Index 126
Drugs and Their Uses
For many thousands of years, humans have used a variety of
agents to cure their ills, promote their well-being, relieve their
misery, and control their fertility. Until the beginning of the
twentieth century, these agents were all of natural origin,
including many of plant origin as well as naturally occurring
elements such as arsenic and antimony. The sixteenth century
alchemist and physician known as Paracelsus used mercury
and arsenic in his treatment of syphilis, worms, and other dis-
eases that were extremely common at that time; his cure rates
remain unknown. It is of interest, though, that arsenic trioxide
is still used today, albeit in limited fashion, as an anticancer
agent, and antimony derivatives are used in the treatment of
the tropical disease leishmaniasis.
Our story of modern drug discovery begins with the Ger-
man physician and scientist Paul Ehrlich. Born in 1854, Ehrlich
became interested in the ways in which synthetic dyes, then
becoming a major product of the German fine chemical indus-
try, could selectively stain certain tissues and cellular compo-
nents. He reasoned that such dyes might form the basis for
drugs that would selectively interact with diseased cells and
organisms. One of Ehrlich’s early successes was the arsenical
“606”—patented under the name Salvarsan—as a treatment
for syphilis. Ehrlich’s dream was to create the “magic bullet,” a
drug that would with absolute specificity target only the dis-
eased cell or the disease-causing organism and not affect
healthy tissues and cells. In this he was not successful, but his
research did lay the groundwork for the subsequent great dis-
coveries of the twentieth century, including the discovery of
the sulfonamide drugs and the antibiotic penicillin. The latter
agent saved countless lives during World War II.
From these original advances has come the vast array of
drugs that are available to the modern physician. We are
increasingly close to Ehrlich’s aim of a magic bullet: Drugs can
now target very specific molecular defects in a number of can-
cers, and doctors today have the ability to interrogate the
6
human genome to more effectively match the drug with the
patient. In the next one or two decades, it is almost certain that
the cost of reading an individual genome will be sufficiently
cheap that such “personalized” medicines will become the rule
rather than the exception. These drugs do, however, carry very
significant costs of both discovery and delivery, thus raising
significant social issues of availability and equity of medical
treatments.
Despite these current discoveries, it is interesting to note
that a very significant fraction of the currently available drugs,
notably antibiotics and anticancer agents, are either natural
products or are derived from natural products. Such chemicals
have been forged in the crucible of evolution and have pre-
sumably been derived by nature for very specific biological
purposes.
The twenty-first century will continue to produce major
advances in medicines and medicine delivery. Nature, however,
is also a resilient foe. Diseases and organisms develop resistance
to existing drugs so that new molecules must be constantly
sought. This is particularly true for anti-infective and anti-
cancer agents. Additionally, new and more lethal forms of
existing diseases can rapidly develop and with the ease of travel
can easily assume pandemic form. Hence the current concerns
about avian flu. Also, diseases that have been previously dor-
mant or geographically circumscribed may suddenly break out
worldwide. In this way, for instance, an Ebola epidemic would
produce many casualties. Finally, there are serious concerns for
man-made epidemics through the deliberate spread of existing
biological disease agents or through the introduction of a lab-
oratory-manufactured or rejuvenated organism such as small-
pox. It is therefore imperative that the search for new
medicines continues.
All of us at some point in life will take a medicine, even if
it is only aspirin for a headache. For some individuals, drug use
will be constant throughout life, as in the current treatment of
7
AIDS, or will take place only during a certain stage, such as a
woman taking hormonal contraceptives during her period of
fertility. Quite generally, as we age we will likely be exposed to
a variety of medications from childhood vaccines to pain-
relieving drugs in a terminal disease. It is not easy to get accu-
rate and understandable knowledge about the drugs that are
used to treat diseases. There are, of course, highly specialized
volumes and periodicals for the physician and scientist, but
these demand a substantial knowledge basis and experience to
be fully understood. Advertising on television provides only
fleeting information and is usually directed at a single drug;
hence the viewer has no means to make a critical or knowl-
edgeable evaluation. The intent of this series of books—Drugs:
The Straight Facts—is to present to students a readable, intelli-
gent, and accurate description of drugs available for specific
diseases, why and how they are used, their limitations, and
their side effects. It is our hope that this will provide students
with sufficient information to satisfy their immediate needs
and give them the background to ask intelligent questions of
their health care providers when the need arises.
David J. Triggle, Ph.D.

University Professor
School of Pharmacy and Pharmaceutical Sciences
State University of New York at Buffalo
An in-depth account of drugs and drug discovery can be

found in John Mann, The Elusive Magic Bullet: The Search for
the Perfect Drug. New York: Oxford University Press, 1999.
8
Introduction
A little over a century ago, oncology—the study of cancer and
its treatment—was just getting its start. Some cancers could be
treated with surgery, but there were no real drugs for cancer
treatment, and a diagnosis of cancer was pretty much a death
sentence. Today, oncology is a medical specialty and a detailed
education in cancer and its treatments takes years to complete.
The diagnosis of cancer has changed from a message of hope-
lessness to one of increased survival, better quality of life, and,
in some cases, even hope for a complete cure.
In the past century, so much has happened to improve
cancer therapy that no single book can adequately cover it all.
The uses of surgery, radiation, drugs, and other therapies have
all made major strides. This book is designed to introduce the
reader to some of the drugs that are currently available.
Remember that these drugs are only part of the therapies avail-
able to any cancer patient, and a course of treatment may
include all or some of the other treatment options available.
Each type of cancer is best suited to a particular combination
of treatments, and each patient’s case has its own unique fea-
tures, requiring a customized approach. Only the basic meth-
ods of activity, known risks of use, and unique characteristics
of each drug will be described. A doctor should be consulted to
put this information into context for any individual patient.
Keep in mind that the information in this book describes
the anticancer drugs available in the United States at the time
of printing. Some of these drugs may or may not be available
in other countries, and some drugs available overseas have not
been approved for use in the United States. When they are
available overseas, the drugs mentioned in this book may have
a different brand name.
9
1
The Cellular Basis
of Cancer
The word cancer comes from the Greek word karkinos, for “crab.” The
physician Hippocrates gave the disease this name around 460 B.C.E.
because blood vessels growing through the tumors he observed
reminded him of the shape of crab claws. Hippocrates’s was not the
first written record of the disease. The earliest known description of
cancer was found in an ancient Egyptian papyrus written between
3000 and 1500 B.C.E. Clearly, this disease was recognized a long time
ago, inspiring many different attempts through the years to explain
its cause and to cure it. Early physicians saw that surgery, when pos-
sible, often did not stop the return of this devastating disease, so they
turned to the natural world for substances to help eliminate cancer
regrowth.
As long ago as 300 B.C.E., extracts of ginger root may have been
used to treat skin cancers, and the Greek physician Dioscorides
(c. 40–90 C.E.) recorded the use of red clover and the autumn crocus,
Colchicum autumnale, to treat a variety of cancers. These and many
other records of attempted therapies eventually led to the develop-
ment of modern drugs to fight cancer. For example, in 1938, scien-
tists looked further into the ancient Roman use of the autumn
crocus and successfully extracted the anticancer drug colchicine.
The search for drugs to treat cancer truly entered the modern era
as scientists gained an increased understanding of how cells—espe-
cially cancer cells—worked. In this chapter, you will learn about the
10
The Cellular Basis of Cancer 11
cell, how cancer cells differ from normal cells, and how cancer
drugs take advantage of cellular mechanisms to eliminate can-
cer cells.
CELL STRUCTURES AND THEIR FUNCTIONS

Although some groups of cells in the body have specialized
characteristics, all cells share basic structures that are necessary
for performing the same basic functions. Cancer cells share
these structures, too, but the way they control their functions
and respond to environmental changes differs from the meth-
ods that normal cells use. Cancer cells will be discussed later;
normal cell properties are described here first.
The cell is surrounded by a flexible, permeable membrane
that organizes the cell’s structure and controls its interaction
with its environment. The membrane is a fluid environment
with specialized proteins suspended in it. These proteins
respond to chemical signals from both inside and outside the
cell. Inside the cell, the cytoplasm (a watery fluid) surrounds a
number of important structures, or organelles (Figure 1.1):
• nucleus—where the cell’s genetic material is stored in the

form of a molecule called DNA (deoxyribonucleic acid).
DNA defines how a cell functions during its lifespan, how
and when it will divide, and how long the cell will live.
• mitochondria—these organelles convert nutrients into

usable energy.
• lysosomes—cellular digestive enzymes are found in these

membrane sacs in the cytoplasm. They are used to process
materials for elimination from the cells, and even clean up
the remains of the cell itself when it dies.
• endoplasmic reticulum—this structure is important to pro-

tein and DNA synthesis (production). Cells manufacture
proteins to control almost all their functions and to affect the
12 CANCER DRUGS
function of other cells in their environment. Ribosomes are

small structures often found on the endoplasmic reticulum.
They translate information from the nucleus that is neces-
sary for manufacturing proteins or DNA.
• microtubules—these are hollow, tubular filaments made

of a protein called tubulin. They create some of the
structural elements of the cell. They play an important
role in separating the two cells formed during cell divi-
sion. Centrioles are specialized microtubules that organ-
ize the division of cells.
THE CELL CYCLE AND ITS PHASES

Cancer is generally defined as a growth or tumor that results
from abnormal and uncontrolled cell division. Normal cells of
the body, with a few exceptions, constantly undergo cell division
as old and injured cells die off and are replaced. The process of
controlled growth and death of normal cells is referred to as
homeostasis, and its goal is to maintain a healthy balance in the
life processes of the cells, tissues, and organs of the body.
To achieve this goal, cell growth and division occurs in a
process called the cell cycle, and its steps are carefully con-
trolled by a variety of genetic and molecular feedback mecha-
nisms. In cancer cells, any one or several of these mechanisms
malfunction, allowing the cells’ growth to proceed unchecked.
The cell cycle is an orderly, four-stage process. The cell
starts the cycle when it is engaged in its normal functions. It
eventually prepares to make a copy of itself by entering a phase
in which the the cell’s DNA—its genetic material—replicates,
resulting in duplicate genetic material. The cell returns to its
normal functions for a while before entering the final phase,
when the cytoplasm and duplicate genetic material separates
producing two identical cells.
Normal cells follow the steps of the cell cycle in an orderly
fashion. Cancer cells also follow these steps, but they bypass the
Figure 1.1 The cell and its internal structure.
controls that keep too many of them from entering the cycle at
once and that make them die off when they should.
IMPORTANT FEATURES OF TUMOR GROWTH:

CELL DIVISION
Cancer cells do not stop dividing the way normal cells do.
There are four ways that cancer cells differ from normal cells
that cause them to grow uncontrollably:
1. Normal cells require external growth factors to enter the

cell cycle. External growth factors are substances from the
surrounding environment that trigger division. Cancer
14 CANCER DRUGS
Figure 1.2 The cell cycle.
cells live independently of these growth factors, so they

continually divide.
2. Normal cells limit their division when they come into

contact with other cells. Cancer cells continue to grow
even after touching other cells, resulting in an accumulat-
ing mass of cells.
3. Normal cells eventually die, to be replaced by new ones.

Each time a mature cell divides, a structure called a
telomere at the end of the DNA shortens. When the
telomere is gone, the cell can no longer divide. Young,

immature cells have an enzyme called telomerase that
replaces the telomere until the cell matures. Mature cells
stop producing telomerase, so they eventually die off in a
process of programmed cell death called apoptosis. Cancer
cells, on the other hand, constantly produce telomerase.
This allows them to avoid apoptosis and keep dividing end-
lessly.
4. The DNA of all cells is constantly exposed to destructive ener-

gies, like radiation from the sun, and substances, like waste
materials from the surrounding cells, in the course of a cell’s
life, but normal cells can repair most DNA damage. Normal
cells become unable to continue dividing when their DNA is
damaged beyond their ability to repair it. Cancer cells, how-
ever, are not limited by DNA damage. Not only do they con-
tinue to divide when their DNA is damaged, but they pass on
this genetic damage to future generations of cancer cells.
Each of these characteristics, from the many genetic and

molecular controls of the cell cycle to the growth mechanisms
that go wrong in cancer cells provide an opportunity for a drug
to interfere with the damaged growth processes of cancer.
HOW CANCER DRUGS WORK

All cancer drugs ultimately have the same action: They inter-
fere with or stop the growth of living cells. How they achieve
this goal differs by the cellular functions on which each drug
acts. The same characteristics that contribute to cell growth
can be used against the cell, and chemotherapy takes advan-
tage of these opportunities. The actions of cancer drugs fall
into several broad categories.
Targeting cell function and molecular synthesis

Cells are continually processing nutrients and synthesizing new
molecules from the products of nutrient metabolism. Some
16 CANCER DRUGS
Figure 1.3 Dividing cancer cell. Colored transmission elec-

tron (TEM) of a section through a cancer cell undergoing
mitotic cell division. The cell is in telophase, the last stage
of mitosis. Nuclear envelopes have formed around the dupli-
cate chromosome sets creating two nuclei (green). The cyto-
plasm (orange) contains mitochondria (red). The two
daughter cells are connected by a narrow cytoplasmic bridge
(at center). © Quest/Photo Researchers, Inc.
classes of cancer drugs work because their chemical structure

mimics some nutrient or essential molecule so closely that the
cell incorporates the drug into its processes. Like a wrench
thrown into the gears of a machine, a drug that imperfectly

matches the molecule that the cell needs interferes with its
functions, and eventually causes cell death.
Altering cell signaling and organization

Normal cells send many chemical signals to structures within
the cell and to other cells in the body to start and stop the
processes that sustain life. The cell cycle, for instance, depends
on the coordinated delivery and receipt of numerous signals.
Another example involves the body’s immune system. Nor-
mally, the body’s immune defenses detect cells that are foreign
to the body, such as bacteria, or finds badly damaged cells, and
send signals to immune cells to remove the foreign invader or
the injured cell that cannot start apoptosis. Cancer cells often
do not trigger an appropriate immune response, so some drugs
have been developed to trick the immune system into taking
action against cancerous cells.
Affecting cell surface receptors

Specialized proteins embedded in the cell membrane, called
receptors, continually latch on to specific chemicals in the
environment. Receptors change some cellular functions when
they bind to passing chemical signals. For example, some
chemicals stimulate the cell to grow, others can make the cell
speed up its functions, and other chemicals can signal the cell
that it is time to die. Some cancers continue their growth
because they become very sensitive to growth signals, or
because they become insensitive to the signals that normally
stop cell growth. Certain cancer drugs can block growth sig-
nals from attaching to cell receptors, cutting the cell off from
its growth triggers.
Changing the cancer cell environment

In another strategy related to cell signaling, some cancer drugs
act to change the production or availability of specific
18 CANCER DRUGS
molecules in the body so that cancer cell receptors do not

receive certain chemical signals. For instance, some cancers rely
on the presence of normal body hormones to continue grow-
ing and dividing. Blocking the body’s production of these hor-
mones stops the cancer from growing.
THE BEST WAY TO ADMINISTER A CANCER DRUG

Ideally, drugs that are given to eliminate cancer cells would
only come into contact with cancer cells, to protect normal
cells from damage. In practice, this is rarely possible. While
research continues to look for ways to selectively deliver drugs
HOW DO CANCER DRUGS KNOW TO

ATTACK ONLY CANCER CELLS?
One problem with cancer drugs is that they do not know to
attack only cancer cells. A drug in the body circulates and
contacts most body tissues and cells. The reason that
chemotherapy does not kill all the normal cells is mostly
because of two useful cell characteristics:
1. Normal cells have repair mechanisms that can help
them recover from damage.
2. Cancer cells generally cannot repair themselves
effectively.
Even though they can repair themselves, some normal cells
die from exposure to cancer drugs, or cannot function well even
after repair. Normal cells that divide often are most at risk.
These would include the cells that line the stomach and intes-
tines, hair follicle cells, and bone marrow cells. This accounts
for many of the bad side effects (adverse effects) of cancer
drugs, including nausea, vomiting, hair loss, and other prob-
lems. Modern therapy with cancer drugs is usually given with
treatments to prevent or manage many of these adverse effects.
Figure 1.4 Chemicals for cancer treatment. © Bernard

Annebicque/CORBIS SYGMA
to their intended targets, most cancer drugs today are

circulated throughout the body. Like many other drugs, cancer
drugs may be given orally (by mouth) as capsules or tablets.
Once in the digestive system, they are absorbed and eventually
travel throughout the body in the bloodstream. Most
chemotherapy, however, is given by intravenous (in a vein)
injection, sending the drug directly into the bloodstream.
When this is done by slowly dripping a drug solution into a
vein, it is called intravenous infusion.
Since there are few options for changing the way cancer
drugs are introduced to the body, other methods have been
created to improve the drugs’ impact on cancer cells. Most can-
cer drugs are dosed in regimens, or patterns of administration,
that are timed both to affect cancer cells in the vulnerable
phases of their growth cycle and to allow the noncancerous
cells of the body to recover. Regimens are also devised to
20 CANCER DRUGS
SARCOMA, LEUKEMIA, MYELOMA,

CARCINOMA—WHY ALL THE
DIFFERENT WORDS FOR CANCER?
Cancers can be classified in two ways: by the type of tissue
from which they arise or by the location in the body from
which they start to grow. The first way is known as classifica-
tion by histology and is defined internationally. The second
method of classification is not very useful to doctors, but the
general public may find it easier to talk about cancers as
being in the breast, or lung.
There are five major histological classifications:
Carcinoma—These cancers grow from epithelial tissue,
which is tissue that makes up the outer and inner lin-
ing of the body. Carcinomas account for as much as 90
percent of all cancers.
Sarcoma—These cancers develop in supportive and struc-
tural body tissues, like bones, muscles, tendons, carti-
lage, and fat.
Myeloma—These cancers develop in the plasma cells of
the bone marrow. These are cells that produce some of
the proteins that circulate in the bloodstream.
Leukemia—These cancers are also called liquid cancers
or blood cancers. They start in the bone marrow. They
cause an overproduction of white blood cells that do
not reach their mature form, but they can also cause
cancerous growth of red blood cells.
Lymphoma—These cancers originate in the organs and
tissues of the lymphatic system, including lymph
nodes, spleen, or tonsils. Since lymph vessels circulate
all through the body, a lymphoma may develop in the
lymph system of any organ, such as the stomach,
breast, or brain.
Table 1.1 Cancer Drug Classes and their Characteristics
Class Characteristic
Alkylating agents Share a similar chemical
structure
Antimetabolites Target cell metabolism
Natural products Derived from plant source
Hormones and hormone antagonists Mimic the body’s hormones or
block them
Molecularly targeted agents Target particular cellular
chemicals
Biological response modifiers Affect the body’s immune system
response
Miscellaneous agents Variety of mechanisms,
structures, and sources
combine several cancer drugs. Combination therapy tries to

use drugs that each affects a different cell function to weaken
cancer cells as much as possible. In a variation of combination
therapy, called adjunct therapy, the combination regimen is
administered before or after surgery or radiation therapy. The
regimen is timed to produce the greatest therapeutic benefit
with the least damage to the patient.
Classes of Cancer Drugs

There are many logical ways to group cancer drugs to make
them easier to understand. Some of these categories group
chemically similar drugs together, some group the drugs based
on the cell functions they target, and other categories group the
drugs by origin.
2
Alkylating Agents
The first modern cancer chemotherapy agents were discovered as a
result of the development of chemical warfare agents during World
War I (1914–1918). On December 2, 1943, during World War II, Ger-
man bombers attacked American tankers and munitions ships in
Bari Harbor off the southeastern coast of Italy. Sixteen ships sank
and four more were damaged, setting off at least two major explo-
sions. Hundreds of men were pulled out of the oily, burning waters.
The oil-covered survivors appeared fine at first, but soon began
to complain of internal problems, stinging eyes, and skin lesions.
Four died that day, nine the next day, and by the end of the month,
83 of the 617 survivors were dead.
One of the ships had been secretly carrying 100 tons of mustard
gas. This chemical was used during World War I as a weapon to cause
severe blistering of the skin, eyes, and lungs of soldiers exposed to it.
It gets its name from the mustard-like smell of the impure chemical;
once purified, it is odorless and colorless. Although most of the mus-
tard gas in the Bari Harbor incident burned off in the fires following
the explosions, some of it dissolved in the floating oil, causing the
only American mustard gas casualties of World War II.
Autopsies showed that the bone marrow and lymphatic tissues of
these men were damaged by the gas. As a result, they produced fewer
red blood cells (erythrocytes), white blood cells (leukocytes), and
immune system cells (lymphocytes) than normal. This observation
led researchers in 1943 to use nitrogen mustards to treat Hodgkin’s
disease and lymphocytic lymphoma, cancers related to the overpro-
duction of cells from the bone marrow and lymphatic tissues.
22
Alkylating Agents 23
Figure 2.1 Mustard gas warning poster from World War II.
Source: National Museum of History, Washington, D.C.
Because of the secret nature of the wartime weapons program,

the results of this medical research were not published until
1946.
Initial results were very exciting, because the drug
caused a dramatic regression of advanced lymphomas, but
unfortunately, the tumors always returned. Despite the dis-
appointing lack of a cure, research with chemicals related to
24 CANCER DRUGS
mustard gas, continued, eventually leading to successful

advances with combined cancer therapies in the 1960s.
Research into the nitrogen mustards gave rise to a whole
family of chemically related compounds used to treat a vari-
ety of cancers. Today, these alkylating agents continue to be
the most widely used anticancer drugs.
DRUGS IN THE CATEGORY OF ALKYLATING AGENTS

The earliest members of this class were called nitrogen mus-
tards, since they all shared part of the chemical structure of the
original chemical warfare agent known as mustard gas. The fol-
lowing Figure 2.2 demonstrates this structure and the similar-
ities between the first alkylating agents.
Later alkylating agents departed more and more from
these early chemical structures, but they successfully acted on
cancer through similar mechanisms. Table 2.1 summarizes
these agents.
HOW DO ALKYLATING AGENTS WORK?

DNA is like a paired string of pearls, and each pearl is a mole-
cule called a base. The string is built from a sugar called
“deoxyribose” and from phosphorous and oxygen groups
called “phosphates.” Attached to the deoxyribose molecules in
the “string” are four kinds of nitrogen-containing bases or
“pearls”: adenine (A), guanine (G), cytosine (C), and thymine
(T). These bases can be sorted into two groups: purines and
pyrimidines. Adenine and guanine are purines, which are
larger than the pyrimidines cytosine and thymine. There are
other purines and pyrimidines that are used as building blocks
for other molecules in a cell, but these are the only ones that are
used to create DNA strands.
The two strands of DNA are joined by bonds between the
complementary bases of purines and pyrimidines. The purine
adenine (A) always bonds to the pyrimidine thymine (T) on
the opposite strand. Guanine (G) always bonds to cytosine
Figure 2.2 Chemical structures of some early alkylating agents.

Note their similarity to the first agent in the class, nitrogen mus-
tard (mechlorethamine).
(C). This specific bonding, or pairing, is critical for the for-

mation of stable DNA molecules that control the life processes
of cells.
Groups of paired bases form genes. The genes act like
codes that tell the cell how to function.
Alkylating agents work directly on DNA to prevent cancer
cells from reproducing. These agents are active in all phases of
the cell cycle. There are three ways that alkylating agents inter-
fere with the function of DNA:
1. In the first mechanism, the alkylating agent attaches short

organic molecules called alkyl groups to DNA bases. This
26 CANCER DRUGS
Table 2.1 The Alkylating Agents
Category Generic name Trademark name

(alternative name) (manufacturer or distributor)
Nitrogen mustards Mechlorethamine Mustargen® (Merck)

Melphalan Alkeran® (GlaxoSmithKline)
(L-PAM, phenylalanine
mustard)
Chlorambucil Leukeran® (GlaxoSmithKline)
Cyclophosphamide Cytoxan® (Bristol-Myers Squibb)
Neosar® (Sicor Labs)
Ifosfamide Ifex® (Bristol-Myers Squibb)
Ethyleneimines and Hexamethylmelamine Hexalen® (MGI Pharma)

methylenimines (altretamine)
Thiotepa (generic; produced by various
manufacturers)
Alkyl sulfonates Busulfan Myleran® (GlaxoSmithKline)

Busulfex® (ESP Pharma)
Nitrosoureas Carmustine (BCNU) BiCNU® (Bristol-Myers Squibb)

Lomustine (CCNU) Gliadel® (Guilford Pharmaceuticals)
CEENU® (Bristol-Myers Squibb)
Streptozocin Zanosar® (Sicor Pharmaceuticals)
Tetrazines Dacarbazine (DTIC) DTIC-DOME® (Bayer Pharmaceuticals)

Temozolomide Temodar® (Schering-Plough)
Metal salts Cisplatin Platinol®, Platinol-AQ®

(Bristol-Myers Squibb)
Carboplatin Paraplatin® (Bristol-Myers Squibb)
Oxaliplatin Eloxatin® (Sanofi Aventis)
Many of these agents are also available in generic form through various manufacturers.
Figure 2.3 The relationship between bases, genes, DNA, and

chromosomes.
results in the DNA being broken apart by the cell’s own

repair enzymes when they try to replace the damaged
bases (see Figure 2.4).
2. Alkylating agents cause atoms in the DNA molecule to

bond differently from the way they normally do. This pre-
vents the two strands of DNA from temporarily separat-
ing the way they should when the process of cellular
reproduction begins (see Figure 2.5).
3. Alkylating agents cause the bases in the DNA molecule to

pair up incorrectly. This leads to mutations that impair or
destroy the cell’s function (see Figure 2.6).
28 CANCER DRUGS
Figure 2.4 Alkylating agents attach alkyl groups to DNA bases,

causing them to break apart.
Alkylating agents are approved to treat leukemias that are

chronic; non-Hodgkin’s lymphoma; Hodgkin’s disease; mul-
tiple myeloma; and lung, breast, ovarian, brain, and other
cancers.
NITROGEN MUSTARDS
There are several nitrogen mustards in use as cancer treat-
ments, including mechlorethamine, melphalan, chlorambucil,
cyclophosphamide, and ifosfamide. Mechlorethamine was the
prototype for the alkylating agents. It is not often used today
except in combination regimens for the treatment of
Hodgkin’s disease. It is sometimes used topically (on the skin)

causing them to bond differently.
to treat mycosis fungoides, a slowly progressing lymphoma

that causes red patches on the skin that eventually develop into
tumors. The most important adverse effect of
mechlorethamine is myelosuppression (suppression of the bone
marrow’s production of many types of blood cells). It can also
cause blood clots and injury to the vein at the time of injection.
Melphalan and chlorambucil were created in the hope of
synthesizing drugs that would act more specifically on tumor
cells, sparing normal cells. Although that goal was not entirely
realized, both of these drugs are often used in the treatment of
several cancers. Melphalan is used to treat multiple myeloma
and ovarian cancer—either as a single agent or in combination
30 CANCER DRUGS

causing them to mispair.
with other cancer drugs. Chlorambucil is used to treat chronic

lymphocytic leukemia, and malignant lymphomas. Like
mechlorethamine, melphalan and chlorambucil cause myelo-
suppression as their most common adverse effect.
Cyclophosphamide is the most widely used alkylating
agent and may actually be the most widely used cancer drug. It
was the first cancer agent developed to be administered as a
prodrug: a drug that required the body’s metabolism to change
the drug to its active form. It quickly demonstrated that it
worked against a variety of cancers, and the diseases for which
Figure 2.7 Ethyleneimine (thiotepa) and methyleneimine

(altreatamine) are both chemically similar to alkylating agents..
it is currently approved include malignant lymphomas, multi-

ple myeloma, leukemias, advanced mycosis fungoides, neurob-
lastoma, adenocarcinoma of the ovary, retinoblastoma, and
breast carcinoma. Myelosuppression and alopecia are impor-
tant adverse effects of this drug, which can also cause damage
to the heart muscle when used in high doses.
Ifosfamide, like cyclophosphamide, is a prodrug that
works against a variety of cancers. It is approved for use in the
treatment of germ cell testicular cancer and bone and soft tis-
sue sarcomas. This drug is excreted from the body in the urine,
and can cause hemorrhagic cystitis, a condition in which the
lining of the bladder becomes inflamed and bleeds. To prevent
this, a drug called mesna is given prior to or along with the
ifosfamide dose.
ETHYLENEIMINES AND METHYLENEIMINES

The ethyleneimines and methyleneimines, which include
thiotepa and altretamine, incorporate a simple, nitrogen-based
32 CANCER DRUGS
WHAT IS AN APPROVED USE?

In 1906, the U.S. government passed the Food and Drug Act,
which prohibited interstate commerce in misbranded foods
and drugs. This happened at a time when sanitary inspections
of meatpacking plants were poor in quality, if they were done
at all, and when government oversight of drug production was
nonexistent. The act was meant to improve these conditions,
but unfortunately it did not define the necessary guidelines for
oversight, nor did it empower any government body to take
legal action. In 1937, the maker of Elixir Sulfanilamide sub-
stituted diethylene glycol—antifreeze—for a safer solvent and
killed 107 patients, most of them children. Partly in response
to this tragedy, the government passed the Food, Drug, and
Cosmetic Act of 1938. This act allowed the Food and Drug
Administration (FDA) to take action against companies that
could not prove the safety of the drugs they sold. Over the
years, the FDA’s role in the regulation of drugs sold in the
United States has expanded. Drugs are not only tested for
safety, but companies also have to prove that a drug is effec-
tive before they can sell the product.
Although a drug manufacturer can only advertise the use
of a drug for its approved indication (FDA-approved use), a
doctor is free to use his or her professional experience and
judgment in the use of any approved drug. This means that a
doctor may prescribe a drug for a disease that it is not
approved for, or at a dose different from the approved one.
This is a common practice and a necessary one. No company
is capable of testing a cancer drug for use with every possible
cancer. Doctors who are familiar with the way these drugs work
and who understand the nature of the cancer they are treating
can determine which drugs will be effective against the dis-
ease. They share this information with other doctors, even
publishing their observations so that patients can benefit from
the best possible treatments.
molecule into their overall chemical structure, while remaining

similar to the rest of the alkylating agents. Thiotepa is similar
to mechlorethamine, but does not irritate the tissues it con-
tacts. It is approved for use in the treatment of specific cancers
of the breast, ovary, and bladder. It has been effective in the
treatment of some lymphomas, but newer treatments are pre-
ferred over thiotepa.
Although altretamine is chemically similar to the other
alkylating agents, its specific mechanism of action is not well
understood. It shares the typical adverse effects of this class of
drugs, including myelosuppression. In addition, it often causes
sensory neuropathy (degeneration of the nerves that sense
touch, temperature, or pain) in the hands and feet. Taking vita-
min B6 (pyridoxine) can help avoid the nerve damage, but may
reduce the drug’s effectiveness against cancer.
ALKYL SULFONATE
The alkyl sulfonates differ in chemical structure from the rest
of the alkylating agents by including a group of atoms that con-
tain sulfur and oxygen. Busulfan is currently the only alkyl sul-
fonate used as a cancer treatment.
Busulfan was manufactured in an attempt to create an
alkylating agent that would be less toxic than
mechlorethamine. It has a limited range of activity against can-
cer, and is indicated only for the palliative (easing symptoms
without curing) treatment of chronic myelogenous leukemia.
Unfortunately, myelosuppression is its most common adverse
event, and it can occasionally cause a fatal liver disorder.
NITROSOUREAS
Nitrosoureas include carmustine (BCNU), lomustine
(CCNU), and streptozocin. They have a chemical structure
derived from the nitrogen mustards.
Carmustine is used to treat multiple myeloma and cer-
tain lymphomas when given by injection. A special form of
34 CANCER DRUGS
Figure 2.8 Busulfan contains a chain of carbon atoms

connected to the oxygen-sulfur group.
carmustine is used to treat brain tumors. A thin wafer of a

polymer material is saturated with carmustine and the wafer
is implanted directly into the brain near the tumor. The
drug slowly seeps out of the wafer and is absorbed by the
tumor cells. In its injectable form, carmustine often causes
delayed myelosuppression that may be prolonged. At high
doses, it commonly causes serious toxicity (a poisonous
effect) that affects the lungs, brain, or liver. These adverse
effects are avoided by using the wafers instead of the
injectable form.
Lomustine is used to treat lung and kidney cancers, certain
lymphomas, and brain tumors. Like carmustine, it commonly
causes delayed and prolonged myelosuppression.
Streptozocin is approved to treat a type of cancer of the
pancreas. It sometimes causes serious renal (referring to the
kidneys) toxicity, along with the usual effects of the nitrogen
mustards.
TETRAZINES
The tetrazines, which include dacarbazine (DTIC) and temo-
zolomide, were synthesized in the laboratory from the struc-
ture of the nitrogen mustards. Like the nitrogen mustards, they
are effective alkylating agents.
Dacarbazine is one of the few cancer drugs that work against
the skin cancer melanoma. In addition to myelosuppression, it
can cause a liver toxicity that is sometimes slow to develop and

may be fatal.
Temozolomide is available in capsule form to treat brain
tumors. Myelosuppression, nausea, and vomiting are common
side effects in patients who take this drug.
METAL SALTS
The metal salts include cisplatin, carboplatin, and oxaliplatin.
Although these drugs are alkylating agents, they do not share a
chemical structure with the nitrogen mustards. Instead, they
get their ability to interfere with the structure of DNA from the
existence of an atom of platinum in their molecule. The plat-
inum is highly reactive and readily forms bonds with parts of
the DNA molecule. Remember that like other cancer drugs,
these alkylating agents will affect all cells in the body.
Cisplatin was the first of the platinum compounds found
to be active against cancer. This drug may be best known as
being part of the treatment regimen for Lance Armstrong, the
champion bicycle rider who not only won the grueling Tour de
France seven times, but also won his fight against testicular
cancer. It is approved for use in advanced testicular, ovarian,
SIDE EFFECT OR ADVERSE EFFECT?

Strictly speaking, a side effect is any unwanted effect of a
drug, whether it is harmful or not. An adverse effect is not
only unwanted, but harmful. When the U.S. Food and Drug
Administration (FDA) evaluates a drug for efficacy and safety,
it weighs the good and the bad before approving or rejecting
the drug. Although all the adverse effects listed for some of
these drugs may be frightening, the drugs’ benefits outweigh
the bad effects. Experience has helped doctors find ways to
manage and treat the adverse effects of drugs so that patients
can tolerate their treatment better.
36 CANCER DRUGS
and bladder cancers, in combination with other cancer drugs.

It causes severe effects on the nerves and the kidneys as well as
severe nausea and vomiting during therapy, requiring very
careful dosing and monitoring of patients who take it. Cis-
platin’s effect on the nerves can cause deafness to develop. Cis-
platin is such an effective anticancer agent, however, that
carboplatin, another platinum-containing molecule, was cre-
ated in an attempt to improve on the toxicity problems. Car-
boplatin is not only less toxic than cisplatin at effective doses,
but offers more predictable dosing. It can replace cisplatin in
many of its uses, and is approved for the treatment of ovarian
cancer. Its major adverse effect is myelosuppression. Carbo-
platin causes some of the same toxic reactions that cisplatin
does, but less severely and less frequently.
Oxaliplatin is the newest member of this group of alkylat-
ing agents. It is approved for the treatment of cancers of the
colon and rectum. It is less toxic to the kidneys than cisplatin,
and it affects the nerves differently. Oxaliplatin does not alter
hearing as cisplatin can, but it causes numbness, discomfort,
and pain that can take many months to go away. In addition, it
can cause prickling, blistering, and peeling of the palms of the
hands and the soles of the feet, a collection of symptoms
known as hand-foot syndrome.
ADVERSE EFFECTS OF ALKYLATING AGENTS

Nitrogen mustard gas was useful as a chemical warfare agent
because of its extremely irritating effect on human tissues.
Victims of exposure experienced painful blistering and peel-
ing of their skin and mucous membranes. Administered as an
anticancer treatment, alkylating agents are manufactured for
safe administration usually as intravenous injections or as
tablets to be taken orally. Even so, local irritation and injury at
the site of injection is common with some of these drugs.
Alkylating agents can also cause myelosuppression. This can
pose a problem for patients, especially if they are not being
treated for leukemia or lymphoma. A lack of normal bone

marrow function can lead to immunosuppression (weakened
immune system function) and an increased risk of infection.
Alopecia (hair loss) and anorexia (prolonged loss of appetite)
are also common adverse effects with the use of alkylating
agents.
3
Antimetabolites
Around the time that scientists were first working on using the
nitrogen mustards to “poison” cancer cells, a pathologist at Chil-
dren’s Hospital in Boston tried a different strategy to eliminate can-
cer. In the mid-1940s, Dr. Sidney Farber noticed that children with
leukemia who were given large doses of the vitamin folic acid to
boost their red blood cell production suffered a rapid acceleration of
their cancer. He concluded that blocking the action of folic acid in
the body would stop the disease. Farber acquired several folic acid
antagonists (agents that oppose the action of another chemical). A
chemical called aminopterin, given to him by the drug company
Lederle, improved the condition of 10 out of 16 seriously ill children
with leukemia.
The report of Farber’s findings in the prestigious New England
Journal of Medicine excited a great deal of interest in his discovery.
A local charitable group donated money to help Farber study this
potential cure for leukemia further. The story of one of his patients,
identified only as Jimmy, captured the sympathy of the nation and
inspired many people to donate money to buy Jimmy a television
set so he could watch his favorite team, the Boston Braves, play
baseball.
Farber is remembered today for the work that led to the devel-
opment of methotrexate, which is still used to treat leukemia; for cre-
ating the Children’s Cancer Research Foundation, known today as
the Dana-Farber Cancer Institute; and for inspiring the creation of
the Jimmy Fund, which continues to raise money for cancer research
in the 21st century.
38
Antimetabolites 39
Figure 3.1 Dr. Sidney Farber. © National Library of Medicine
Since Farber’s time, other researchers have discovered

drugs that block different functions involved in cell growth and
replication. Because they ultimately stop normal cellular
metabolism, these drugs were called antimetabolites. This
chapter discusses how these chemicals fool the cell into using
these chemical look-alikes with deadly consequences for
tumors.
40 CANCER DRUGS
ANTIMETABOLITE DRUGS
Table 3.1 lists the currently available antimetabolite cancer
drugs in the United States. They are all analogs (chemical com-
pounds that are structurally similar to, but slightly different
from, another compound) of chemicals that are normally
essential for cellular functions.
How Do Antimetabolites Work?

The antimetabolite drugs mimic compounds that cells nor-
mally need to carry out their functions, but they are just dif-
ferent enough that they stop these processes. Unable to carry
out the processes necessary for life, the cells die. Understanding
how these analogs work will require some knowledge about
what DNA and RNA are made of.
In Chapter 1, we discussed the double-stranded structure
of DNA. DNA provides a code from which cells get the infor-
mation they need to manufacture all the proteins they need to
sustain their activities. Antimetabolite drugs disrupt the stable
DNA structure, making it impossible for the cell to continue
the metabolic processes that keep it alive.
RNA is a single-stranded chain of molecules very similar
to DNA. The string of the RNA strand is built from the sugar
ribose instead of the deoxyribose used in DNA. Instead of the
base thymine, RNA uses the base uracil. RNA is the molecule
that the cell uses to decode the genes in DNA. Therefore, RNA
is critical to the production of every protein created by a cell.
Some of the antimetabolite drugs affect both RNA and DNA.
RNA and DNA are referred to as nucleic acids, since they are
both found in the nucleus of the cell.
Folic Acid Analogs, or Antifolates

Folic acid is an essential dietary nutrient for humans. Cells use
folic acid to manufacture several critical molecules, including
purines. The folic acid analogs methotrexate and pemetrexed
specifically interfere with the normal use of folic acid by cells.
Antimetabolites 41
Table 3.1 Antimetabolic Drugs in the United States
Many of these agents are also available in generic form through various manufacturers.
Category Generic name Trademark name
(alternative name) (manufacturer or distributor)
Folic acid analogs Methotrexate sodium (generic; produced by various
manufacturers)
Pemetrexed Alimta® (Eli Lilly and Company)
Pyrimidine analogs Fluorouracil (generic; produced by various

(5-fluorouracil, 5-FU) manufacturers)
Floxuridine FUDR® (Roche)
(fluorodeoxyuridine)
Cytarabine (cytosine (generic; produced by various
arabinoside) manufacturers)
Capecitabine Xeloda® (Roche)
Gemcitabine Gemzar® (Eli Lilly and Company)
Purine analogs and Mercaptopurine Purinethol® (GlaxoSmithKline)

related inhibitors (6-mercaptopurine, (also generic; produced by variou
6-MP) manufacturers)
Thioguanine (generic; GlaxoSmithKline)
Pentostatin Nipent® (SuperGen)
Cladribine Leustatin® (Ortho Biotech)
Fludarabine Fludara® (Berlex Laboratories)
As with all anticancer drugs, normal cells are affected, too, but
they are usually better able to recover from the drug’s effects
than cancer cells are.
In a normal cell, an enzyme converts folic acid to a form
that the cell can use as it makes the purines it needs. Antifolates
fool cancer cells in two important ways:
• Cells that try to take up folic acid from their environment

incorporate the antifolate instead;
• Once inside, the cell tries to use the antifolate the same way
it normally uses folic acid, but is unable to change the
42 CANCER DRUGS
Figure 3.2 The binding of bases in the double strand of DNA.
antifolate drug the same way, ultimately depriving the cell

of purines—crucial DNA building blocks.
Cells constantly and rapidly divide and grow in developing

embryos. The embryo needs folic acid from the mother’s cir-
culation to adequately produce purines for all the new DNA it
is manufacturing. This is why folic acid analogs given to a preg-
nant woman are toxic to the embryo and can cause miscarriage
if taken during pregnancy.
Methotrexate is used for the treatment of gestational
choriocarcinoma, chorioadenoma destruens, and hydatidi-
form mole. These are cancers arising from abnormal fertiliza-
tion and growth of an embryo.
Methotrexate can be used alone or in combination with
other anticancer agents to treat breast cancer, squamous cell
cancers of the head and neck, advanced mycosis fungoides (a
type of lymphoma), and lung cancer, particularly squamous
Antimetabolites 43
cell and small cell types. Methotrexate is also used with other
chemotherapeutic agents in the treatment of advanced-stage
non-Hodgkin’s lymphomas. It is also approved for treating
some noncancerous diseases such as psoriasis and certain types
of arthritis, and may be given orally or intravenously.
Pemetrexed is used, in combination with cisplatin, for
the treatment of malignant pleural mesothelioma. This is a
rare cancer of the cells of a membrane (pleura) that lines the
abdominal cavity, heart, and lungs, and often occurs in
response to asbestos exposure. Pemetrexed is also used as a
single-agent therapy for non-small cell lung cancer
(NSCLC).
Pemetrexed is given by intravenous infusion only. Patients
also receive folic acid and vitamin B12 supplements during
therapy to help their normal cells recover from toxicities.
LUNG CANCER CELLS

Most organs of the body are made up of more than one kind
of cell, and the lungs are no exception. When doctors want to
precisely describe a lung cancer, they try to determine what
kind of lung cell the cancer arose from.
The majority of lung cancer cells fall into to two broad
categories: Small-cell and Non-small cell (NSCLC). About 20
percent of lung cancers are small-cell cancers, and there are
three subtypes of small-cell cancer: Small-cell carcinoma
(also called oat cell cancer), mixed small cell/large cell carci-
noma, and combined small cell carcinoma. Non-small cell
cancer accounts for about 80 percent of lung cancer and
there are nine subtypes. The majority of NSCLC cancers fall
into three of these subtypes: Squamous cell carcinoma, large
cell carcinoma, and adenocarcinoma. There are some other
types of tissue in the lung, but these rarely become cancer-
ous, and account for only a small percentage of lung cancers.
44 CANCER DRUGS
Pyrimidine Analogs
The pyrimidine analogs—which include fluorouracil (5-
FU), floxuridine, cytarabine, capecitabine, and gemc-
itabine—share the ability to either block the cell’s
production of pyrimidines, or be successfully incorporated
into the cell’s DNA or RNA. They interfere with the resulting
DNA’s or RNA’s ability to function normally. Some of these
drugs can do both.
Floxuridine and capecitabine are metabolized by the
liver, which turns them into 5-FU. Their anticancer activi-
ties are caused by the 5-FU that is produced. The cell incor-
porates 5-FU into both RNA and DNA. As a result, cell
growth is impaired. Cells that are actively growing incorpo-
rate these drugs more readily, so tumor cells and the fre-
quently dividing cells of the body (such as those in the bone
marrow, gastrointestinal tract, hair follicles, and nails) are
most affected. The activity of 5-FU is enhanced by a chemi-
cal called leucovorin, and patients often receive these drugs
in combination.
5-FU is given by intravenous injection to treat cancer of
the colon, rectum, breast, stomach, and pancreas. The FDA has
not approved a tablet form of the drug, which is in common
use in other countries. Floxuridine is given by intraarterial (into
the artery) injection into the liver to treat gastrointestinal
tumors that have spread to the liver. Capecitabine is an oral
drug that is used in combination therapy to treat advanced and
metastatic (cancer that has spread to a site in the body that is
distant from where it originated) colon and breast cancers.
Diarrhea can be a serious problem for patients who take this
drug.
Gemcitabine both inhibits the cell enzymes that create the
pyrimidine bases and replaces cytosine in the manufacture of
DNA, effectively stopping the production of any DNA strand
into which it is incorporated. It is used in combination therapy
for advanced or metastatic breast and non–small cell lung
Discovering Diverse Content Through
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learned the above-mentioned Doctrine[1103], which, upon the
Authority of such a Tradition, countenanced by some Passages in the
Revelations[1104], and one Text in St. Paul, was embraced and held by
the most eminent Men for Piety and Learning, at that time, in the
Church; and, among the rest, by Irenæus, and Justin the Martyr.
And yet such a Doctrine is now rank Heresy in the Church of Rome.
But, by declaring it such, have they not overset their own System,
which places Tradition upon a Level with the Canonical Books of the
Scripture? Can they allege a more antient How little Tradition
Tradition, one more universally received, or to
equally countenanced by Scripture, in favour of be depended upon.
the many traditional Articles of Faith, which they have obtruded
upon the World? Papias declares, he received the above-mentioned
Doctrine of those who had learned it immediately of the Apostles. If
such a Tradition be rejected as false, what other has a Right to be
admitted as true? If we deny or question St. Peter’s having been at
Rome, Tradition, and the Authority of Irenæus (for all the others
have copied from him), are immediately produced against us. But
what Weight either ought to bear, the Case before us sufficiently
demonstrates.
To return to Apollinaris: It is very certain, that he held and taught
the Doctrine of the Millenarians; but it is no less certain, that such a
Doctrine was not condemned, as Baronius pretends[1105], by the
Council of Rome in 378. since many eminent Men in the Church held
it, and Sulpitius Severus among the rest, after that Council, without
being deemed Heretics on that score. The The Apollinarists
Sentence pronounced against Apollinaris, and con-
his Disciples, by the Council of Rome, was demned by several
Councils.
confirmed by a Council held the same Year at
Alexandria[1106], by an Oecumenical Council assembled at
Constantinople in 381. and by the Council of Antioch in 379[1107].
However, the Apollinarists, though thus condemned and deposed by
all the Councils of the East and West, as we read in Gregory
Nazianzen[1108], still kept their Ground, till Recourse was had to the
Secular Power. For the Emperor Theodosius, at Penal Laws enacted
the Request of Nectarius Bishop of against them.
Constantinople, enacted a Law, dated the Tenth of March 388.
forbidding the Apollinarists to hold Assemblies, to have any
Ecclesiastics or Bishops, or to dwell in the Cities[1109]. As this Law was
executed with the utmost Rigour, at least against the leading Men of
the Party, who were banished the Cities, and confined to the
Deserts[1110], the Apollinarists were in a few Years reduced to a very
small Number, when they begged to be admitted to the Communion
of the Catholic Church, which was in the End granted them by
Theodotus[1111], who governed the Church of Antioch, from the Year
416. to 428. But as their Conversion was owing not to Conviction,
but Persecution, they still held in their Hearts the same Sentiments,
which ever must happen in the like Case; nay, and privately instilled
their Errors into the Minds of many, whose Faith had been, till that
time, untainted[1112]. It was to these pretended Catholics, or
disguised Apollinarists, that the Eutychian Heresy, and that of the
Monothelites, of whom I shall speak hereafter, owed their Birth[1113].
Hence the Emperor Marcian, by an Edict in 455. declared the
Eutychians to be Apollinarists, and consequently liable to the same
Penalties[1114]. As for Apollinaris himself, he died about the Year 392.
having maintained, to the Hour of his Death, the same Sentiments,
in which he had lived; and, with them, the same outward
Appearance, at least, of a most holy and exemplary Life[1115]; which
is all the Authors of those Times Will allow him.
While Damasus, and the other Western New Disturbances
Bishops, were wholly intent upon suppressing raised by Ursinus.
the Heresy of Apollinaris, and restoring the Eastern Churches to their
former Tranquillity, the Antipope Ursinus, laying hold of that
Opportunity, arrived privately at Milan, and there joined the Arians,
upon their promising to support him with the whole Power of their
Party[1116]. But Ambrose, who then governed that Church, and kept a
watchful Eye over the Flock committed to his Care, gave immediate
Notice of their clandestine Meetings, and pernicious Designs, to the
Emperor Gratian, who soon after ordered Ursinus to quit Italy, and
confined him to Cologne[1117]. During his Exile his Partisans were not
idle; they found the Emperor Gratian, who in 375. had succeeded his
Father Valentinian I. warmly engaged in favour of Damasus: they
well knew, that so long as he continued in that Disposition, it would
be in vain to solicit the Return of Ursinus, or to put up any Petition in
his Behalf. In order therefore to estrange the Damasus falsly ac-
Mind of the Emperor from Damasus, they cused, but cleared
suborned a Jew, named Isaac, who had by
the Emperor.
embraced the Christian Religion, but was then
returned to Judaism, to accuse him before the Civil Magistrate of an
heinous Crime, which I find not specified by any of the Antients. But
the Emperor, taking upon himself the judging of that Cause, soon
discovered the Innocence of the Accused, and the Malice of the
Accuser; and therefore, honourably acquitting the former, and
punishing the latter according to his Deserts, confined him to a
Corner of Spain[1118].
This Attempt on the Reputation of Damasus was not the only
Thing that gave him great Uneasiness at this time. The Emperor
Valentinian had transferred, as I have related above, the Power of
judging Bishops, such at least as were concerned in the Schism of
Ursinus, from the Civil Magistrate to the Bishop of Rome. But several
Bishops, though deposed by him, still Some Bishops, de-
maintained themselves in their Sees, with open posed by Damasus,
Force, in Defiance of his Sentence, and the keep their Sees.
Imperial Law. Among these were the Bishop of Parma, and
Florentius Bishop of Puzzuolo, who, for their Attachment to Ursinus,
had been both deposed by Damasus, and other Bishops assembled
at Rome[1119]. The Donatists too, notwithstanding the severe Laws
enacted against them by several Emperors, had got Footing in Italy,
and in Rome itself, where they were known by the Names of
Montenenses, and Rupenses, on account of their assembling in a
Church or Oratory, which they had among the neighbouring Rocks
and Mountains[1120]. They had a Bishop of their own, either sent from
Africa, or ordained by Bishops sent from thence for that Purpose.
Claudian, who governed them at this time, was their Fifth Bishop of
Rome[1121]. The Emperor ordered him to be sent back to Africa,
whence he came. But though he had been several times imprisoned,
in order to oblige him by that means to return, he could not even so
be prevailed upon to abandon his Flock; but continued at Rome,
perverting many there, and rebaptizing all he could pervert[1122]. To
put a Stop to these Evils, the Bishops of Italy, The Italian Bishops
assembling at Rome, had recourse to the recur to the
Emperor Gratian, acquainting him with the Emperor.
Conduct of the contumacious Bishops, and earnestly intreating him
to cause the Law, commanding the Bishops to be judged by the
Bishop of Rome, and not by the Civil Magistrate, which he himself
had enacted with his Father, to be put in Execution. By that Law, the
Emperor, in all Likelihood, only intended to confirm, with respect to
the Bishop of Rome, the Canons of the Church, appointing the
Metropolitan, with his Council, Judge of the Bishops of his Province
in Ecclesiastical Causes. But the Bishops, assembled on this Occasion
at Rome, attempted to extend the Authority of the Bishop of Rome,
far beyond the Bounds to which the Emperors and Canons had
confined it. For, in their Letter to Gratian, they Their letter to him.
suggested the following Regulations as
necessary for the Tranquillity of the Church, and intreated him to
establish them by Law: 1. That if any, who had been condemned by
the Bishop of Rome, or other Catholic Bishops, should, after such
Condemnation, presume to keep their Churches, they should be
banished from the Territories of the Cities, where they had been
Bishops. 2. That such as should refuse, when lawfully summoned, to
appear before the Bishops, should be obliged, by the Prefect of Italy,
or his Vicar, to repair to Rome, to be judged there. 3. That, if the
accused Bishop resided in a distant Province, he should be obliged,
by the Judges of the Place, to appear before his Metropolitan; and, if
his Metropolitan was suspected as partial, or prejudiced against him,
he might be allowed to appeal to the Bishop of Rome, or to a
Council of Fifteen neighbouring Bishops; but, if the Accused was
himself a Metropolitan, he should either repair to Rome, or appear
before such Judges as the Bishop of Rome should appoint; and,
when thus condemned, submit to the Sentence[1123]. In Behalf of the
Bishop of Rome in particular they begged, in the What they demand
same Letter, that, as he was above other in
Bishops by the Prerogative of the Apostolic See, particular for the
Bishop of Rome.
though upon a Level with them as to the
Ministry, he might not be obliged to appear before the Civil
Magistrate, since other Bishops had been exempted from their
Jurisdiction, but before a Council, or that the Emperor would reserve
to himself the Cognisance of what concerned him, leaving to the
ordinary Judges the Power of examining Facts and Witnesses, but
not the Authority of pronouncing Sentence[1124]. The Emperor’s
What Answer the Emperor returned to the Answer.
Council, we know not; but, in a Rescript, addressed to the Vicar
Aquilinus, after summing up the Heads of the Letter from the
Council, and severely reprimanding his Officers for their Neglect, in
not causing the Imperial Law to be put in Execution, he confirms the
Rescript address’d to Simplicius, which I have mentioned above;
commands the Bishop of Parma, Florentius of Puzzuolo, and
Claudian the Donatist, with all those who shall be condemned by the
Councils, as Disturbers of the Quiet of the Church, to be driven from
their Dioceses, and banished an Hundred Miles from Rome: he
grants all the Council had desired, with respect to the judging of
Bishops; but requires the Bishop of Rome to act with the Advice of
Five or Seven other Bishops; and, lastly, he forbids Persons of
infamous Characters, or known Slanderers, to be admitted as
Informers or Witnesses against Bishops[1125]. In this Rescript he
takes no notice of what the Council had asked for the Bishop of
Rome in particular.
From these Pieces, which are still extant, it is In what Sense the
manifest beyond all Dispute, as the Reader must Pope above other
have observed, that, in the Year 378. when this Bishops.
Council was held, no Prerogative was yet discovered in the Pope,
peculiar to him, and not common to all Bishops, besides that of
Rank, which arose from the Dignity of his See, that is, from his being
Bishop of the Metropolis of the Empire; for, in that respect alone, the
Bishops, who composed the Council, acknowleged him to be above
them; nay, by declaring themselves, in express Terms, equal to him
as to the Ministry, they seem to have taken particular Care, that no
Room or Pretence should be left for his claiming a Superiority in any
other respect. And how great would their Surprize have been, had
Damasus, in hearing that Part of their Address to the Emperor,
started up, and, protesting against it, as derogatory to his
Prerogative, declared, that, to him all Power was given in Heaven
and on Earth; that, so far from being equal to him, they, and all
other Bishops, were but his Deputies and Delegates; that the Power,
Authority, and Jurisdiction, which they enjoyed, were derived to
them from the Plenitude of his! Had he talked in this Strain, the
whole Council would have concluded him delirious. And yet these are
the Sentiments of his Successors; these the very Words, with which
they and their Divines have expressed them[1126]; so that it is now
reckoned Heresy not to believe what in the Fourth Century it had
been deemed Madness to have gravely uttered. The Power he now
It would perhaps have seemed still more strange claims unknown in
and surprising to the Fathers of the Council, the
Time of Damasus.
however prejudiced in his Favour, if Damasus,
instead of gratefully acknowleging their Regard for him in petitioning
the Emperor, that he might not be judged by the Civil Magistrate,
but either by a Council, or the Emperor himself, had severely
rebuked them as Strangers to, or Betrayers of, his inherent Right,
acquainting them, that, in virtue thereof, all Men were to be judged
by him, but himself by no Man[1127]; that the greatest Monarchs were
his Slaves and Vassals, and he King of Kings, Monarch of the World,
sole Lord and Governor both in Spirituals and Temporals[1128]; that he
was appointed Prince over all Nations and Kingdoms[1129]; that his
Power excelled all Powers[1130]; that it was necessary to Salvation for
every human Creature to be subject to him[1131]. And yet these are
the Notions, that have been uttered by his Successors, and the very
Terms in which they were uttered. In the Age I am now writing of,
they had been looked upon no otherwise than the Ravings of a
distempered Brain; but they are now held by the Church of Rome,
and her Divines, as Oracles, and inserted as such into her Canons.
Bellarmine owns, that, in the Fourth Century, the Pope was still
subject to the Emperors, nay, and to the Civil Magistrate, without the
least Distinction between him and other Vassals. But this Subjection,
says he, in his Apology against King James[1132], the Emperors
exacted by Force, because the Power of the Pope was not known to
them. Nor to any body else, he might have added, since the Writers
of those Times seem to have been no better acquainted with the
Power of the Pope than the Emperors; at least, they take no Notice
of it, even in describing, as some of them have done, the State of
the Church at the time they writ, and relating the Customs, Laws,
and Practices, that then obtained. Besides, how could the Power of
the Pope be unknown to the Christian Emperors, if it was one of the
chief Tenets of the Christian Doctrine? Neither Damasus, nor any of
his Predecessors, can be justly charged with Bashfulness, in
acquainting the World with the Power they had or claimed. We may
further observe here, that the Emperor requires the Bishop of Rome,
in judging according to the Power granted him, to act with the
Advice of Five or Seven other Bishops: a plain Proof, that he was as
little acquainted with the Pope’s Infallibility, as with his Power.
The Council of the Italian Bishops, assembled A new Accusation
at Rome, no sooner broke up, than the brought against
Emissaries and Partisans of Ursinus began to Damasus.
raise new Disturbances in that City, by stirring up the Pagans against
Damasus, and, at the same time, charging him with things, to use
the Expression of the Council of Aquileia, not fit to be uttered by a
Bishop, nor heard by such an Emperor as Gratian[1133]. Anastasius
writes, that he was accused of Adultery by the Two Deacons
Concordus and Callistus[1134]. And truly, that some Crime of that
Nature was laid to his Charge, is pretty plain, from the Terms in
which it was expressed by the Council. Valerian, then Governor of
Rome, immediately acquainted the Emperor with the Accusation[1135];
but what Part Gratian acted on this Occasion, we are not told by any
antient Writer. We read in the Pontificals, and most of the modern
Writers, that the Cause was referred by the Emperor to the Council
then sitting at Aquileia; and that Damasus was declared innocent by
all the Bishops who composed it. But, as neither The Council of
is related by any credible Author, I am inclined Aquileia writes to
to believe, that Gratian took no Notice of the the
Emperor in his
Charge, in Compliance with the Request of the Behalf.
Bishops assembled at Aquileia; for, by a Letter,
they earnestly intreated him not to hearken to Ursinus, because his
giving ear to him would occasion endless Disturbances in Rome;
and, besides, they could by no means communicate with a Man who
thus wickedly aspired to a Dignity, to which he had no Claim or Title;
who, by his scandalous Behaviour, had incurred the Hatred of all
good Christians; who had impiously joined the Arians, and, together
with them, attempted to disturb the Quiet of the Catholic Church of
Milan[1136].
Towards the Latter end of the Pontificate of A great Council as-
Damasus, Two great Councils were held, the one sembled at Con-
at Constantinople in 381. and the other at Rome stantinople, by the
Emperor
in 382. The former was assembled by the Theodosius.
Emperor Theodosius, who, after having put the
Orthodox in Possession of the Churches, which till his Time had been
held by the Arians in the East, where he reigned, summoned all the
Bishops within his Dominions to meet at Constantinople, in order to
deliberate about the most proper Means of restoring an intire
Tranquillity to the Church, rent and disturbed not only by several
Sects of Heretics, but by the Divisions that reigned among the
Orthodox themselves, by that especially of Antioch, the most antient
of all, which, from that Church, had spread all over the Empire, and
occasioned rather an intire Separation, than a Misunderstanding
between the East and the West, the former communicating with
Meletius, and the latter with Paulinus, as I have related above. In
this Council many weighty Matters were transacted, and several
Canons established, some of which, namely, the Second and Third,
deserve to be taken Notice of here. For, by the Second, the Council
renewed and confirmed the antient Law of the Church, authorized by
the Fourth, Fifth, and Sixth Canons of the Council of Nice,
commanding the Bishops of each Province to be ordained by those
of the same Province, and such of the neighbouring Provinces, as
they should think fit to call in; directing all Ecclesiastical Matters to
be settled, all Disputes to be finally decided by a Council composed
of the Bishops of the Province, or at least of the Diocese, that is, of
all the Provinces under the same Vicar; and strictly forbidding the
Bishops of one Diocese to concern themselves, under any Colour or
Pretence whatsoever, with what happens in another[1137]. By this
Canon the Privilege, formerly granted to the See of Rome by the
Council of Sardica, was revoked, and all Appeals which revokes the
from the Council of the Diocese forbidden. By Privilege granted to
the Third Canon the See of Constantinople is the See of Rome
by the Council of
declared first in Rank and Dignity after that of Sardica.
Rome[1138]. Some Greek Writers have pretended,
that, by this Canon, the Two Sees were declared in every respect
equal; but that Zonaras himself owns to be false and groundless[1139].
It is to be observed, that the Council of Constantinople gave Rank
and Honour to that See, but no Jurisdiction. It was to the Council of
Chalcedon that the Bishops of Constantinople owed their Authority
and Jurisdiction; for by that Council they were impowered to ordain
the Metropolitans of the Dioceses of Pontus, Asia, and Thrace[1140].
The Reasons alleged by Baronius to prove the Third Canon of the
Council of Constantinople supposititious[1141], are quite frivolous; and
it is certain beyond all Dispute, that the Bishops of that City
maintained ever after the Rank, which the above-mentioned Canon
had given them. In a short time the Bishop of Constantinople, taking
Advantage of that Canon, and of the Deference that is naturally paid
to the Bishop of the Imperial City, extended his Jurisdiction over all
the neighbouring Provinces, nay, and over the whole Eastern Empire,
as we shall observe in the Sequel of this History.
The Canons of this Council were, without all The Council writes
doubt, sent, according to Custom, to the to
Western Bishops for their Approbation, probably the Western
Bishops.
with the Letter which the Council writ to them
concerning the Heresy of Apollinaris[1142]. And yet Pope Leo the Great
writes, that the Third Canon was never notified to the Church of
Rome[1143]; and Gregory the Great, that the Canon condemning the
Eudoxians, which was the first, had never been received at
Rome[1144]: but Gregory perhaps meant nothing else, than that the
Canon he mentions was of no Authority at Rome. As for Leo, it is
hard to conceive what he meant by saying, that the Third Canon was
not known to the Church of Rome; for he could not but know, that
the Bishop of Constantinople held the Second Rank in the Church,
and the First in the East, since his own Legates, whose Conduct he
intirely approved of, owned him to have an indisputable Right to that
Rank; nay, Eusebius Bishop of Dorylæum in Phrygia maintained, that
it was with the Consent and Approbation of Leo himself that the See
of Constantinople enjoyed that Honour.
The Authority of this Council has ever been The Authority of
great among the Greeks, who style it an this
Oecumenical Council, and had often recourse to Council among the
Greeks,
it as such in the Council of Chalcedon[1145]. The
Bishops of the Hellespont speak of it with the greatest Respect and
Reverence, in a Letter they writ to the Emperor Leo[1146]. As for the
Latins, I find a great Disagreement among the and the Latins.
Popes themselves concerning the Authority of
this Council; nay, the greatest of them all disagrees even with
himself about it. The Legates of Pope Leo rejected its Canons,
alleging that they had never been inserted in the Book of the
Canons[1147]. In like manner the Popes Simplicius and Felix II.
speaking of the Councils which they received, name those only of
Nice, Ephesus, and Chalcedon[1148]. Gregory the Great writes, that
the Church of Rome had neither the Acts nor the Canons of the
Council of Constantinople; that the Condemnation of the
Macedonians was the only thing done by that Council which they
admitted; and that as to other Heresies condemned there, they
rejected them, as having been condemned before by other
Councils[1149]. But he declares elsewhere, and often repeats it, that
he received the Four Oecumenical Councils, as he did the Four
Gospels[1150], naming the Council of Constantinople in the Second
Place. In the same Manner, and with the same The Popes at Var-
Words, were the Four Oecumenical Councils iance among and
received by Gelasius, and several Popes before with
themselves about
him, as well as by Martin I. and several others it.
after him: so that the Council of Constantinople
is, according to some Popes, of equal Authority with the Gospel;
according to others, of no Authority at all: nay, it is thus by the same
Pope at one time extolled, at another undervalued. Let Baronius and
Bellarmine reconcile these Contradictions, if they can.
That this Council was assembled by the This Council was
Emperor Theodosius, is affirmed by all the assembled by the
Writers who speak of it[1151], nay, and by the Emperor, and not by
Bishops who composed it[1152]. And yet Baronius Damasus.
has the Assurance to assert, as a Thing not to be questioned, that it
was convened by Damasus[1153], which none of the Antients have so
much as once named: and this Assertion he founds upon the
Authority of the universally exploded Acts of Damasus; of certain
Manuscripts, which he knows very little of, and nobody else any
thing; and of a Passage in the Acts of the Sixth Oecumenical Council,
where it is said, that Theodosius and Damasus opposed with great
Firmness the Macedonian Heresy; whence the Annalist concludes, by
what Rules of Logic I leave the Reader to find out, that the Council,
which condemned the Heresy of Macedonius, was convened by the
Authority of Damasus, backed by that of the Emperor[1154].
Christianus Lupus, more honest than Baronius, tho’ no less attached
to the See of Rome, ingenuously owns, that the Council was
assembled by the Emperor alone; but adds, that Damasus confirmed
it[1155]; which is true, if he means no more than that Damasus
accepted the Decrees made by the Council; for it was not his, but
the Emperor’s Approbation, that gave them a Sanction; and
accordingly they writ, not to him, but to the Emperor, acquainting
him; by whose Command they had been called together, with the
Decrees they had made, and requesting him to confirm them with
his Seal and Sentence[1156]. This Council consisted of an Hundred and
Fifty Bishops, among whom were Thirty-six Macedonians, whom
Theodosius had particularly summoned, hoping to reunite them with
the Catholics[1157]. No mention is made of Letters or Deputies sent
either by Damasus, or by any of the Western Bishops; and
Theodoret assures us in Two different Places[1158], that Theodosius
only assembled the Eastern Bishops. Meletius of Antioch presided;
for Gregory of Nyssa styled him in full Council, our Father and
Head[1159]. Upon his Death (for he died while the Council was sitting)
that Honour was conferred on Gregory Nazianzen, appointed by the
Emperor and the Council Bishop of Constantinople[1160]; but he
resigning, soon after, his new Dignity, his Successor Nectarius was
named to preside in his room[1161].
One of the chief Motives that induced Theodosius to assemble so
numerous a Council at Constantinople, was, to hear what Remedy
they could suggest against the Schism of the Church of Antioch,
which caused such Jealousies between the East and the West as
seemed to forebode an imminent Rupture[1162]. But before the
Fathers of the Council entered upon that important Subject, Meletius
died; and his Death, which ought to have put an End to the present
Disturbances, served only to increase them, and engage the
contending Parties more warmly in the Dispute. It had been agreed
by Meletius and Paulinus, that the Survivor should be sole Bishop of
all the Orthodox at Antioch[1163]. Socrates and Sozomen add[1164], that
Six Presbyters, who it was most likely might be one Day raised to
that See, bound themselves by a solemn Oath not to vote for any
other, nor to accept themselves the Episcopal Dignity, so long as
either of the Two lived. However, Meletius was The Disturbances in
no sooner dead, than some of the Prelates the Church of
present at the Council moved for chusing him a Antioch
increased.
Successor, which occasioned many long and
warm Debates. Gregory Nazianzen, elected Bishop of Constantinople
a few Days before, exerted all his Eloquence to divert the Council
from a Resolution, which, he said, would prove fatal to the Church,
and kindle a Flame, which perhaps it might never be in their Power
to extinguish[1165]. Several other Prelates, Enemies to Strife and
Contention, falling in with Gregory, spoke to the same Purpose,
exhorting their Collegues, with great Zeal and Eloquence, to put an
End at last to the unhappy Divisions that had so long rent the
Church, by allowing Paulinus, already stricken in Years, to govern
peaceably the remaining Part of his Life[1166]. But the far greater Part
were for a new Election, offering no other Reason to recommend
such a Step, but that the East, where our Saviour had appeared,
ought not to yield to the West[1167]. So that the Resolution of giving a
Successor to Meletius was taken merely out of Pique to the Western
Bishops, who, having the Bishop of Rome at their Head, had begun
to treat their Brethren in the East with great Haughtiness, and
assume an Air of Authority that did not become them; but that had
been better resented on any other Occasion than on this.
The Resolution being taken, Flavianus, a Flavianus ordained
Presbyter of the Church of Antioch, was named Bishop of Antioch.
by the Council, and, with the Approbation of the Emperor, and of all
the Meletians at Antioch, ordained in that City. He is commended by
the Writers who lived in or near those Times, as a Man of an
exemplary Life, and extraordinary Piety, as a zealous Defender of the
Orthodox Faith, and Opposer of the Arian Heresy, as a Mirror of
every Sacerdotal Virtue; and, barring the Right of Paulinus, the most
worthy and deserving Person the Council could name to succeed the
great Meletius[1168]. These, and other like Encomiums, bestowed
upon Flavianus by the Writers of those Times, leave no room to
doubt but Socrates and Sozomen were misinformed in naming him
among the Six Presbyters who took the Oath I have mentioned
above; the rather as no notice is taken of such an Oath by his most
inveterate Enemies, in the many Disputes that arose about his
Ordination. Gregory Nazianzen, who had been Greg. Nazianzen
lately preferred to the See of Constantinople, resigns the
and had accepted that Dignity with no other Bishoprick
of Constantinople.
View, but to remove all Jealousies, and restore a
good Understanding between the East and the West, being sensible
that the electing of a new Bishop in the room of Meletius would
widen the Breach, and obstruct all possible Means of an
Accommodation, resigned his Dignity, and, to the inexpressible Grief
of his Flock, retired both from the Council and City[1169]. In one of his
Orations[1170], he ascribes this Resolution to the Divisions that
reigned among the Bishops, declaring that he was quite tired with
their constant quarreling and bickering among themselves, and
comparing them to Children at Play; whom to join in their childish
Diversions, would be degrading a serious Character. Upon the
Resignation of Gregory, Nectarius was chosen to Nectarius is chosen
succeed him; but, as to the Particulars of his in
Election, they are variously related by Authors, his room.
and foreign to my Purpose. He was a Native of Tarsus in Cilicia,
descended of an illustrious and senatorial Family, but at the Time of
his Election still a Layman, and Prætor of Constantinople; nay, he
had not been baptized[1171].
The same Year that the Eastern Bishops met The Council of
at Constantinople, by the Command of Aquileia writes to
Theodosius, the Western Bishops met at Theodosius in
favour
Aquileia, by the Command of Gratian. While the of Paulinus.
latter were yet sitting, News was brought of the
Death of Meletius, and at the same time they received certain
Intelligence of the Resolution which the Council of Constantinople
had taken of appointing him a Successor. Hereupon having
dispatched the Business for which they had met, and condemned
Palladius and Secundianus, the only Two Arian Bishops now in the
West, they dispatched some Presbyters into the East, with a Letter
to the Emperor Theodosius, wherein, after expressing the Joy it had
given them to hear that the Orthodox in those Parts were at last
happily delivered from the Oppression of the Arians, they
complained of the Hardships Paulinus had met with, whom they had
always acknowleged as lawful Bishop of Antioch, put the Emperor in
mind of the Agreement between Paulinus and Meletius, and
concluded with intreating him to assemble an Oecumenical Council
at Alexandria, as the only Means of restoring Tranquillity to the
Church, and settling a perfect Harmony amongst her Members[1172].
Before this Letter reached the Emperor, the Council of
Constantinople was concluded, and the Bishops returned to their
respective Sees. However, Theodosius recalled some of them, in
order to govern himself by their Advice in granting or denying the
Western Bishops their Request[1173]. But the And the Bishops of
Election of Flavianus being in the mean time Italy in favour of
known in the West, the Bishops of the Vicariate Maximus.
of Italy, them assembled in Council with Ambrose Bishop of Milan at
their Head, writ a long Letter to Theodosius complaining of that
Election, openly espousing at the same time the Cause of Maximus
against Nectarius, the new Bishop of Constantinople, and
threatening to separate themselves intirely from the Communion of
the Eastern Bishops, unless Maximus was acknowleged lawful Bishop
of that City, or at least an Oecumenical Council was assembled to
examine the Claims of the Two Competitors, and to confirm with
their joint Suffrages the disputed Dignity to him, who had the
best[1174]. They also desired, in the same Letter, to have the Contest
between Paulinus and Flavianus decided.
Maximus, surnamed the Cynic, because he Who Maximus was,
had from his Youth professed the Philosophy, and how chosen
and wore the Habit, of that Sect, was a Man of a Bis-
hop of
most infamous Character, and had been publicly Constantinople.
whipt in Egypt, his native Country, and confined
to the City of Oasis, for Crimes not to be mentioned[1175]. Being
released from his Banishment, he wandered all over the East, and
was every where equally abhorred and detested on account of his
matchless Impudence and scandalous Manners[1176]. At last he
repaired to Constantinople, where he had not been long, when, by
one of the boldest Attempts mentioned in History, he caused himself
to be installed and ordained Bishop of that City: for the Doors of the
Church being broken open in the Dead of the Night, by a Band of
Egyptian Mariners, he was placed on the Episcopal Chair in the
profane Dress of a Cynic, by some Bishops whom his Friends had
sent out of Egypt for that Purpose. But the People, and some of the
Clergy, in the adjoining Houses, being alarmed at the Noise, and
crouding to see what occasioned it, Maximus and his unhallowed
Crew thought fit to withdraw, and complete the Ceremony in a Place
better adapted to such a Scene of Profaneness, the House of a
Player on the Flute[1177]. Maximus, thus ordained, in equal Defiance
of the Imperial Laws and Canons of the Church, had the Assurance
to claim the See of Constantinople as his Right, and to protest
against the Election of Gregory Nazianzen, and likewise of Nectarius,
who was chosen upon the Resignation of Gregory, tho’ they had
both been named to that Dignity by the Council of Constantinople,
that is, by all the Eastern Bishops. But no Regard being had to his
Protest, nay, his Ordination being declared null by the Council, and
he driven out of the City by the Populace, and rejected with
Indignation by the Emperor, he had recourse to the Bishops of the
Vicariate of Italy, then assembled in Council with Ambrose Bishop of
Milan at their Head, as I have observed above. He is acknowleged
These giving an intire Credit to the Accounts of by
the lying and deceitful Cynic, as they were quite
unacquainted with what had passed in the East, Ambrose, and the
not only admitted him to their Communion, but, Italian Bishops.
without farther Inquiry or Examination, acknowleged him for lawful
Bishop of Constantinople, and writ the above-mentioned Letter to
Theodosius in his Behalf[1178]. We must not confound this Council
with that of Aquileia, as I find most Writers have done: for the latter
was composed of almost all the Western Bishops under Valerian
Bishop of the Place; whereas the Council I am now speaking of,
consisted only of the Bishops of the Vicariate of Italy, under the
Bishop of Milan their Metropolitan. It is surprising that Ambrose, and
the other Bishops of that Council, should not have been better
informed with respect to the Ordination of Maximus, since Acholius
Bishop of Thessalonica, with Five other Bishops of Macedon, had, at
least a Year before, transmitted to Damasus a minute Account of it,
agreeing in every Particular with that which I have given above from
Gregory Nazianzen[1179]. The Letter from the The Emperor’s Ans-
Council caused no small Surprize in Theodosius: wer to their Letter.
he was sensible they had suffered themselves to be grosly imposed
upon; but, not judging it necessary to undeceive them, he only told
them, in his Answer to their Letter, that the Reasons they alleged did
not seem sufficient to him for assembling an Oecumenical Council,
and giving so much Trouble to the Prelates of the Church; that they
were not to concern themselves with what happened in the East, nor
remove the Bounds, that had been wisely placed by their Fore-
fathers between the East and the West; and that, as to the Affair of
Maximus, by espousing his Cause they had betrayed either an
unwarrantable Animosity against the Orientals, or an inexcusable
Credulity in giving Credit to false and groundless Reports[1180].
Upon the Receipt of this Letter, the Italian A Council of all the
Bishops, finding Theodosius no ways disposed to Western Bishops
assemble an Oecumenical Council, applied to assembled at Rome.
Gratian, who not only granted them Leave to meet at Rome, the
Place they chose, but dispatched Letters to all the Bishops both in
the East and West, giving them Notice of the Time and Place, in
which the Council was to be held, and inviting them to it[1181]. But of
all the Eastern Bishops, Two only complied with this Invitation; viz.
Epiphanius Bishop of Salamis in the Island of Cyprus, and Paulinus,
whom all the West acknowleged for lawful Bishop of Antioch. The
Western Bishops were all present, either in Person, or by their
Deputies; and Damasus presided[1182]. But, as to the Transactions of
this great Assembly, we are almost intirely in the Dark; for all we
know of them is, that they unanimously agreed not to communicate
with Flavianus, the new Bishop of Antioch, nor with Diodorus of
Tarsus, or Acacius of Berœa, who had been chiefly instrumental in
his Promotion; that they condemned the Heresy of Apollinaris; and
that, at the Request of Damasus, a Confession of Faith was drawn
up by Jerom, and approved by the Council, which the Apollinarists
were to sign, upon their being re-admitted to the Communion of the
Church[1183]. As for Maximus, they seem to have abandoned his
Cause, being, in all Likelihood, undeceived, with respect to his
Ordination, by Acholius Bishop of Thessalonica, and St. Jerom, who
assisted at the Council, and could not be Strangers to the Character
of Maximus, nor unacquainted with the scandalous Methods by
which he had attained the Episcopal Dignity.
The Resolution they took not to communicate The
with Flavianus, whose Election, though Misunderstanding
imprudently made, was undoubtedly Canonical, between the East
and the West
and had been approved and confirmed by the increased.
Oecumenical Council of Constantinople, not only
increased the Jealousies and Misunderstanding between the East and
the West, but occasioned a great Disagreement, and endless
Quarrels, among the Eastern Bishops themselves. For those who
acknowleged Paulinus, viz. the Bishops of Egypt, of the Island of
Cyprus, of Arabia, insisted upon the Deposition of Flavianus[1184].
Nestorius mentions some Letters, written by the Bishops of Egypt
against Flavianus, with great Virulency, and a tyrannical Spirit, to use
his Expression[1185]. On the other hand, the Bishops of Syria, of
Palæstine, of Phœnicia, Armenia, Cappadocia, Galatia, Pontus, Asia,
and Thrace, not only maintained, with equal Warmth, the Election of
Flavianus, but began to treat their Brethren in the East, who had
joined the Western Bishops against them, as Schismatics, as
Betrayers of their Trust, as Transgressors of the Canons of Nice,
commanding the Elections and Ordinations of each Province to be
made and performed by the Bishops of the same Province, and all
Disputes concerning them to be finally decided in the Place where
they had begun[1186]. This Schism occasioned great Confusion in the
Church, which continued till the Year 398, when Chrysostom, after
having, with indefatigable Pains, long laboured in vain to bring about
an Accommodation between the East and the West, had at last, soon
after his Promotion to the See of Constantinople, the Satisfaction of
seeing his pious Endeavours crowned with Success, as I shall relate
in a more proper Place.
From this whole Account it is manifest, as the No Regard paid by
Reader must have observed, that the Orientals the Eastern Bishops
paid no manner of Regard either to the to the Judgment of
the Pope.
Judgment of the Bishop of Rome, or to that of
the whole Body of the Western Bishops, assembled in Council under
him. For though they well knew the Bishop of Rome, and his
Collegues in the West, to be warmly engaged in favour of Paulinus,
yet they refused to acknowlege him, even after the Death of
Meletius; and therefore raised Flavianus to the See of Antioch, in the
room of Meletius, and confirmed that Election in an Oecumenical
Council. The Western Bishops exclaimed against it, desiring it might
be referred to the Decision of a General Council. But not even to that
Demand would the Orientals agree, thinking, as they declared in
their Answer, that there was no Occasion for a Council, since
Flavianus had been chosen and ordained by the Bishops of the
Diocese, which was all the Canons of Nice required. They therefore
exhorted them to divest themselves of all Prejudices, to sacrifice all
private Affections to the Peace and Unity of the Church, and to put
an End to the present, and prevent all future, Disputes, by
approving, with their joint Suffrages, an Election which had been
approved and confirmed by an Oecumenical Council[1187].
To return to Damasus: He was the first who The Custom of ap-
introduced the Custom, which his Successors pointing Vicars
took care to improve, of conferring on certain intro-
duced by Damasus,
Bishops the Title of their Vicars, pretending and on what Oc-
thereby to impart to them an extraordinary casion.
Power, enabling them to perform several Things,
which they could not perform in virtue of their own. Acholius Bishop
of Thessalonica was the first who enjoyed this Title, being, by
Damasus, appointed his Vicar in East Illyricum, on the following
Occasion: Illyricum, comprising all antient Greece, and many
Provinces on the Danube, whereof Sirmium was the Capital, had,
ever since the Time of Constantine, belonged to the Western Empire.
But, in the Year 379. Dacia and Greece were, by Gratian, disjoined
from the more Westerly Provinces, and added, in favour of
Theodosius, to the Eastern Empire, being known by the Name of
East Illyricum, whereof Thessalonica, the Metropolis of Macedon,
was the chief City. The Bishops of Rome, as presiding in the
Metropolis of the Empire, had begun to claim a kind of Jurisdiction,
or rather Inspection in Ecclesiastical Matters, over all the Provinces of
the Western Empire; which was the first great Step by which they
ascended to the Supremacy they afterwards claimed and
established. This Damasus was unwilling to resign with respect to
Illyricum, even after that Country was dismembered from the
Western, and added to the Eastern Empire. In order therefore to
maintain his Claim, he appointed Acholius Bishop of Thessalonica to
act in his stead, vesting in him the Power which he pretended to
have over those Provinces. Upon the Death of Acholius he conferred
the same Dignity on his Successor Anysius, as did the following
Popes on the succeeding Bishops of Thessalonica, who, by thus
supporting the Pretensions of Rome, became the first Bishops, and,
in a manner, the Patriarchs, of East Illyricum; for they are sometimes
distinguished with that Title. This, however, was not done without
Opposition, the other Metropolitans not readily acknowleging for
their Superior one who, till that time, had been their Equal[1188].
Syricius, who succeeded Damasus, inlarging the Power claimed by
his Predecessor, decreed, that no Bishop should be ordained in East
Illyricum without the Consent and Approbation of the Bishop of
Thessalonica[1189]. But it was some time before this Decree took
place. Pope Innocent I. writes, that his Predecessors committed to
the Care of Acholius, Achaia, Thessaly, the Two Epirus’s, Candia, the
Two Dacia’s, Mœsia, Dardania, and Prævalitana, now Part of Albania,
impowering him to judge and decide the Controversies that might
arise there, and appointing him to be the first among the Primates,
without prejudicing the Primacy of those Churches[1190]. Thus were
the Bishops of Thessalonica first appointed Vicars or Vicegerents of
the Bishops of Rome, probably in the Year 382. for in that Year
Acholius assisted at the Council of Rome, and it was, in all
Likelihood, on that Occasion that Damasus vested him with this new
Dignity. The Contrivance of Damasus was The Institution of
notably improved by his Successors, who, in Vicars improved by
order to extend and inlarge their Authority, the succeeding
Popes.
conferred the Title of their Vicars, and the
pretended Power annexed to it, on the most eminent Prelates of
other Provinces and Kingdoms, engaging them thereby to depend
upon them, and to promote the Authority of their See, to the utter
Suppression of the antient Rights and Liberties both of Bishops and
Synods. This Dignity was for the most part annexed to certain Sees,
but sometimes conferred on particular Persons. Thus was Austin
appointed the Pope’s Vicar in England, Boniface in Germany; and
both, in virtue of the Power which they pretended to have been
imparted to them with that Title, usurped and exercised an Authority
above that of Metropolitans. The Institution of Vicars was, by the
succeeding Popes, improved into that of Legates, or, to use De
Marca’s Expression, the latter Institution was grafted on the
former[1191]. The Legates were vested with a far Legates vested with
greater Power than the Vicars, or, as Pope Leo greater Power than
expresses it, were admitted to a far greater Vicars.
Share of his Care, though not to the Plenitude of his Power[1192].
They were sent on proper Occasions into all Countries, and never
failed exerting, to the utmost Stretch, their boasted Power,
oppressing, in virtue of their paramount Authority, the Clergy as well
as the People, and extorting from both large Sums, to support the
Pomp and Luxury in which they lived.
The Custom of appointing Vicars and Legates may well be alleged
as a remarkable Instance of the Craft and Policy of the Popes, since,
of all the Methods they ever devised (and many they have devised)
to extend and establish their Power, none has better answered their
ambitious Views. But how Bellarmine could lay so much Stress upon
it as he does[1193], to prove, that the Pope has, by Divine Right, a
sovereign Authority and Jurisdiction over all the Churches of the
Earth, is unconceivable. For it is certain, beyond The sending
all Dispute, that such a Custom had never been Legates
heard of till the Time of Damasus, that is, till the no Proof of the
Pope’s
Latter-end of the Fourth Century, when it was universal
first introduced, upon the dismembering of East Jurisdiction.
Illyricum, by Gratian, from the Western Empire.
Damasus did not even then claim that sovereign and unlimited
Power, with which Bellarmine is pleased to vest him, but only a kind
of Inspection over the Provinces of the Western Empire, as Bishop of
the first See. And here I cannot help observing The Disingenuity of
the Disingenuity of Bellarmine, who, in speaking Bellarmine.
of this Institution, expresses himself thus: Leo appointed Anastiasius
Bishop of Thessalonica his Vicar in the East, in the same manner as
the Predecessors of Anastasius had been Vicars to the Predecessors
of Leo[1194]. From these Words every Reader would naturally
conclude, and Bellarmine designs they should, that the Bishops of
Thessalonica had been the Pope’s Vicars from the Beginning, or Time
out of Mind; whereas it is certain, that this Institution had taken
place but a few Years before. Pope Leo I. in conferring on Anastasius
the Vicariate Dignity of his See, as he styles it, declared, that he
followed therein the Example of his Predecessor Syricius[1195], who
first appointed Anysius to act in his stead. But he was doubly
mistaken; for these Vicars were first instituted, as is notorious, by
Damasus, and not by Syricius; and it was not by Syricius, but by
Damasus, that Anysius was vested with that Dignity[1196]. The Bishop
of Thessalonica is styled, by the antient Writers, the Pope’s Vicar in
East Illyricum, which is manifestly confining his Vicariate Jurisdiction
to that District; but Bellarmine extends it at once all over the East,
by distinguishing him with the Title of the Popes Vicar for the
East[1197]. But how little Regard was paid to the Pope’s Authority in
the East, I have sufficiently shewn above.
I find nothing else in the antient Writers concerning Damasus
worthy of Notice, besides his generously undertaking the Defence of
Symmachus, who, being Prefect of Rome in 384. the last Year of
Damasus’s Life, and a sworn Enemy to the Christians, was falsly
accused to the Emperor, as if he had with great Cruelty persecuted
and oppressed them. But Damasus had the Generosity to take his
Part, and clear him, by a Letter he writ to the Emperor, from that
Charge[1198]. This was one of the last Actions of Damasus dies.
Damasus’s Life; for he died this Year on the 10th
or 11th of December, being then in the Eightieth Year of his Age,
after he had governed the Church of Rome for the Space of Eighteen
Years, and about Two Months[1199]. He was buried, according to
Anastasius[1200], near his Mother and Sister, in a Church which he had
built at the Catacombs, on the Way to Ardea; whence that Place,
though Part of the Cœmetery of Calixtus, is by some called the
Cœmetery of Damasus[1201]. He proposed at first being buried near
the Remains of St. Sixtus, and his Companions; but afterwards
changed his Mind, lest he should disturb the Ashes of the Saints[1202].
He caused the Church of St. Laurence, near the Theatre of Pompey,
probably that which his Father and he himself had formerly served,
to be rebuilt, inlarged, and embellished; Whence it is still known by
the joint Titles of St. Laurence and Damasus[1203]. In that Church his
Body is worshiped to this Day. But, how or when it was removed
thither, nobody knows[1204]. Several Decrees are The Decrees
ascribed to Damasus by Gratian, Ivo of Chartres, ascribed
Anastasius, and others, but all evidently forged to him
suppositious.
by some Impostor blindly addicted to the See of
Rome, and quite unacquainted with the Discipline of the Church in
the Fourth Century. In one of them a Canon is quoted from the
Council of Nice, forbidding the Laity to eat or drink of any thing that
was offered to the holy Priests, because none but the Jewish Priests
were allowed to eat of the Bread that was offered on the Altar. We
know of no such Canon; and besides, it is not at all probable, that
the Council of Nice would have restrained the Clergy from sharing at
least with the Poor what was offered them. In another of these
Decrees the Paying of Tythes is commanded, on pain of
Excommunication; whereas it might be easily made appear, that, in
the Fourth Century, the Offerings destined for the Maintenance of
the Clergy were still voluntary. Another Decree supposes, that, by an
antient Custom, all Metropolitans swore Fealty to the Apostolic See,
and could ordain no Bishops till they had received the Pall from
Rome. For the Sake of this, Baronius admits all the rest: but of such
a Custom not the least Mention, or distant Hint, is to be met with in
any antient Writer.
Damasus is ranked by Jerom[1205] among the His Writings in
Ecclesiastical Writers, on account of the many Prose and Verse.
small Pieces he writ, chiefly in Verse; for he had a particular Genius
for Poetry, and was no despicable Poet, if some Compositions
ascribed to him were truly his. He writ several Books, both in Prose
and Verse, in Commendation of Virginity; but neither that, nor any of
his other Works, has reached our Times, besides some Letters, and a
few Epitaphs, Inscriptions, and Epigrams, which have been carefully
collected by Baronius[1206], though it may be justly questioned
whether the several Pieces ascribed to him by that Writer were
written by him. A short History of the first Popes, styled, The
Pontifical of Damasus, and published together with the Councils, has
long passed for the Work of Damasus; but now even Baronius owns
it not to be his; and most Critics are of Opinion, that it was written
after the Time of Gregory the Great; nay, some ascribe it to
Anastasius Bibliothecarius, who flourished in the Ninth Century[1207].
As for his Letters, those to Aurelius of Carthage, to Stephen, styled,
Archbishop of the Council of Mauritania, to Prosper Primate of
Numidia, to the Bishops of Italy, are all spurious, as well as the
Letters to which some of them are Answers, and supposed to have
been forged by that notorious Impostor Isidorus Mercator[1208]. His
genuine Letters are the Two, that are to be found among the Works
of Jerom, to whom they were written; Two to Acholius Bishop of
Thessalonica, published by Holstenius in his Collection of the antient
Monuments of the Church of Rome[1209]; a Letter of great Length to
Paulinus of Antioch, whereof the chief Heads are set down by
Theodoret in his History, as are likewise those of his Letter to the
Orientals concerning Timotheus, the favourite Disciple of Apollinaris.
Several Letters from the Councils, that were held in Rome in his
Time, and at which he presided, are still extant, and may well be
ascribed to him. The Two Letters to Jerom are well worth perusing,
being written in a pure, easy, and elegant Style, and with a great
deal of Spirit, Vivacity, and even Gaiety, though Damasus was then
much advanced in Years, and overburdened with Cares and
Business[1210]. In one of them he declares, that his only Delight was
to read the Scriptures; and that all other Books, however well
written, gave him rather Disgust than Pleasure. Jerom returned to
Rome from the East in 382. with Epiphanius Bishop of Salamis, and
Paulinus of Antioch, to assist at the Council held there. The other
Two returned to their Sees; but Jerom continued Jerom kept at
at Rome, being kept there by Damasus, who Rome,
employed him in answering the Letters he and employed by
him.
received from the Councils of several Churches
applying to him for his Advice[1211]. Damasus, taken with his Learning
and Erudition, and chiefly with the Knowlege he had of the Scripture,
had long before lived in great Intimacy with him, and upon his
leaving Rome writ frequent Letters to him, not thinking it beneath
the Rank he held in the Church to consult him as his Master about
the true Meaning of some difficult Passages in holy Writ[1212]. Thus in
one of his Letters he desires him to explain the Parable of the
Prodigal Son[1213], and in another to interpret the Word Hosanna,
which he says was differently interpreted by different Writers, who
seemed to contradict each other[1214]. In Compliance with this
Request, Jerom writ the Piece on that Subject, which is still extant. It
was likewise at the Desire of Damasus that he corrected the Latin
Version of the New Testament, and revised at Rome the Latin
Version of the Psalms, comparing it with the Greek Text of the
Septuagint. But as to the Letter, with which Damasus is supposed to
have encouraged him to undertake that Work, it is evidently
supposititious, and altogether unworthy of him.
Anastasius ascribes to Damasus the Custom of Psalmody falsly as-
Singing, instead of Reading, the Psalms at Divine cribed to him.
Service[1215]. But it is manifest from Austin, that this Practice was
brought from the East, and first complied with by the Church of
Milan[1216], in the Year 386. that is, Two Years after the Death of
Damasus. So long as Damasus lived, Jerom continued at Rome; but
as, by his Learning and exemplary Life, he was an Eye-sore to the
lewd, ignorant, and haughty Clergy of Rome, or as he styles them,
the Senate of Pharisees[1217], he thought it adviseable to abandon the
City upon the Death of his great Friend and Protector, and retire to
Jerusalem, hoping to find there that Quiet and Tranquillity which he
despaired of being able to enjoy while he dwelt with the Scarlet
Whore[1218], that is, while he lived at Rome. As His Character.
for the Character of Damasus; Jerom styles him,
a Virgin Doctor of the Virgin Church; and, in his Letter to
Eustochium, a Man of great Excellence. Theodoret commends him as
a Man of a holy Life, as one who declined no Fatigue or Labour to
support and maintain the Doctrine of the Apostles, and who struck
the Arians with Terror, though he attacked them at a Distance[1219].
Elsewhere he calls him the famous Damasus[1220], and places him at
the Head of the most celebrated Teachers of Truth, who, till his
Time, had appeared in the West[1221]. That Greek Writer could not be
biassed in his Favour, though Jerom perhaps was. The Orientals
declared, in 431. that they followed the Example of Damasus, and
other Persons eminent for Learning[1222]; and the Council of
Chalcedon, speaking of his Letter to Paulinus of Antioch, styles him
the Honour and Glory of Rome for Piety and Justice[1223]. The Church
of Rome honours him as a Saint, and his Festival is kept in some
Places on the 10th, in others on the 11th of December. But, after all,
that he got the Pontificate by the most horrible Violence and
Bloodshed; that he lived in great State; that he had frequent and
grand Entertainments; that he kept a Table, which, in
Sumptuousness, vied with the Tables of the Emperors themselves;
and all this at the Expence of the Roman Ladies, whose generous
Contributions might have been applied to better Uses; is affirmed by
contemporary and unexceptionable Writers. It is likewise manifest
from the Letters of Jerom, that in his Time the Discipline of the
Church was greatly relaxed; that the Observance of the primitive
Canons was almost utterly neglected; and that Luxury, Ignorance,
and Debauchery, universally prevailed among the Ecclesiastics at
Rome. And this Charge against his Clergy in some degree recoils
upon him, since he appears to have carried the Papal Authority
farther than any of his Predecessors, and therefore might have
restrained and corrected them. Whether his Sanctity may not from
all this be justly questioned, notwithstanding the favourable
Testimony of some antient Writers, I leave the Reader to judge.
Valentinian, SYRICIUS, Arcadius,

Theodosius, Honorius.
Thirty-seventh BISHOP of
Rome.
S yricius, the Successor of Damasus, according Year of Christ 384.
to the Pontificals, and some antient
Monuments quoted and received by Baronius[1224], was a Native of
Rome, the Son of one Tiburtius, had been first Reader, and
afterwards Deacon, under Liberius, and, upon his Death, had
zealously espoused the Cause of Damasus against Ursinus and his
Party. Damasus being dead, he was chosen in his room by the
unanimous Acclamations of the whole Roman People, being at that
time Presbyter of the Church known by the Title of the Pastor,
perhaps the most antient Church in Rome[1225]. Ursinus, who was still
alive, did not fail, upon the Vacancy of the See, to revive his former
Claim; but he was rejected with Scorn and Indignation. Valentinian
the younger, who then reigned in Italy under the Direction of his
Mother Justina, received the News of this Election with great Joy;
and, concluding from the Unanimity of the Electors, the Worth and
Merit of the Person elected, confirmed Syricius in his new Dignity, by
a Rescript dated the 23d of February, and directed to Piaianus, at
that Time either Prefect or Vicar of Rome[1226][N20].
N20. Damasus died on the 10th or 11th of December 384. as I

have related above; and Syricius was chosen the same Year, as we
read in the Chronicle of Prosper. Anastasius therefore, and the
Author of the Pontifical published by Bollandus, as well as
Baronius, were certainly mistaken in affirming, upon what Grounds
I know not, that, upon the Death of Damasus, the See remained
vacant for the Space of 31 or 36 Days[1].
1. Anast. p. 21. Boll. Apr. t. 1. p. 32. Bar. ib. n. 5.
The first Thing I read of Syricius is his His Answer to

answering a Letter or Relation which Himerius, Himerius Bishop
Bishop of Tarragon in Spain, had sent to of Tarragon.
Damasus by Bassianus, a Presbyter of that Church, requiring the
Advice of the Church of Rome concerning some Points of Discipline,
and certain Abuses that prevailed in Spain. Damasus being dead
before the Arrival of Bassianus, Syricius, who had succeeded him,
caused this Relation or Letter to be read, and carefully examined, in
an Assembly of his Brethren, that is, perhaps, of the Bishops who
had assisted at his Ordination; and, having maturely weighed and
considered every Article, he first acquainted Himerius with his
Promotion, and then returned to each the following Answers[1227].
The First was concerning the Sacrament of Baptism, which was by
some Bishops of Spain rejected as null and invalid, when conferred
by an Arian Minister. In Opposition to them, Syricius alleges the
Authority of Liberius, and of the Council of Nice, the Practice of the
Church of Rome, and that of all other Churches both in the East and
West[1228]. Isidorus of Seville takes particular notice of this Point of
Discipline, which he says was established by the Letter of
Syricius[1229]. By the Second Article he forbids the Sacrament of
Baptism to be administred at Christmas, or the Epiphany, on the
Feasts of the Apostles or Martyrs, or at any other Time but Easter,
and during the Pentecost of that Festival, meaning, in all Likelihood,
all Easter time, or the Fifty Days between Easter and Pentecost, or
Whitsuntide; for such, adds he, is the Practice of the Church of
Rome, and of all other Churches. From this Rule, however, he
excepts Children, and all Persons, who are any-ways in Danger[1230].
By the Third Article, he forbids granting the Grace of Reconciliation
to Apostates, that is, forgiving and readmitting them to the
Communion of the Church, except at the Point of Death[1231]. By the
Fourth, a Woman, who, being betrothed to one Man, has received
the Priest’s Blessing to marry him, is debarred from marrying
another. The Fifth Article commands all Persons, who, being guilty of
a Crime, have performed Penance for it, to be treated as the
Apostates, if they relapse into the same Crime; and the Sixth, all
religious Persons, whether Men or Women, guilty of Fornication, to
be dealt with in the same Manner, and, moreover, to be excluded
from partaking of the sacred Mysteries, that is, of the Eucharist,
except at the Point of Death[1232]. How different is the present
Practice of the Church of Rome from that of the same Church in the
Fourth Century! which was perhaps even too severe.
Syricius, by the Seventh Article of his Letter, Priests and Deacons
obliges all Priests and Deacons to observe obliged to observe
Celibacy; and as some had not paid due Celibacy.
Obedience to that Command of the Church, he allows those who
should acknowlege their Fault, and plead Ignorance, to continue in
their Rank, though without Hopes of rising: but as for those who
should presume to defend this Abuse as lawful, he declares them
deposed and degraded from the Rank they held in the Church[1233]:
Pope Innocent I. writing to Exuperius Bishop of Toulouse, quotes and
transcribes great Part of this Article[1234]. The Eighth, Ninth, Tenth,
and Eleventh Articles describe at length the Life which those ought
to have led, who are raised by the Clergy and People to the
Episcopal Dignity, and the Steps or Degrees by which they should
ascend to it. They ought first to have been Readers; at the Age of
Thirty, Acolytes, Subdeacons, and Deacons; Five Years after,
Presbyters; and in that Degree they were to continue Ten Years
before they could be chosen Bishops. Those who had been married
to Two Wives, or to a Widow, are absolutely excluded from ever
sitting in the Episcopal See. Even the Lectors are forbidden, on pain
of Deposition, to marry twice, or to marry a Widow[1235]. These, and
several other less important Regulations, Syricius delivers as general
Rules to be inviolably observed by all Churches, often declaring, that
those who do not readily comply with them shall be separated from
his Communion by the Sentence of a Synod, and strictly injoining the
chief Prelates of each Province to take care they be punctually
observed within the Bounds of their respective Jurisdictions, on Pain
of being deposed, and treated as they deserve. He therefore desires
Himerius to notify his Letter, not only to all the Bishops of his
Diocese or Province, but likewise to those of Carthagena, Bætica,
Lusitania, Galicia, and to all the neighbouring Bishops, meaning
perhaps those of Gaul; for Innocent I. supposes the Decrees of his
Predecessor Syricius to be known to Exuperius of Toulouse[1236]; and
in all Likelihood they were so to others in that Country.
This Letter is the First of all the Decretals acknowleged, by the
Learned, to be genuine, and likewise the First in all the antient
Collections of the Canons of the Latin Church. It is quoted by
Innocent I. and Isidore of Seville, and is the only Letter of the many
ascribed to Syricius, that Dionysius Exiguus has inserted in his
Collection. It is to be found in Father Quesnel’s Roman Code[1237];
and Cresconius quotes no other Decrees of Syricius but what are
taken from this Letter. It is dated the Third of the Ides of February,
that is, the Eleventh of that Month 385. Arcadius and Bauto being
Consuls[N21].
N21. The Jesuit Papebrok highly extols this Letter[1], but, at the
same time, does not think it quite pure and genuine, because the
Date, says he, has been added to it; for the other Letters of
Syricius, and likewise those of his Predecessors, bear no Date. But
can we conclude from thence, that they never had any? Some of
the Letters of Innocent I. are dated, and some without a Date,
and he admits both. The Transcribers contented themselves, for
the most part, with copying the Body of the Letter, and neglected
the rest. Papebrok adds, that the Date ought to have been
expressed thus: Arcadio Aug. et Bautone viro clar. Conss. and not
Arcadio et Bautone viris clarissimis, as it is in that Letter. But might
not this Mistake be owing to the Ignorance of the Transcribers,
who, finding, in the Original, only the Two Letters, V. C. which are
to be met with in many antient Writings, set down viris clarissimis,
instead of viro clarissimo? Papebrok must have observed the same
Mistake in the Letter, which Pope Innocent I. writ to the Council of
Milevum[2], and which he allows to be altogether genuine. For Slips
or Oversights of this Nature, hardly avoidable, no Piece ought to
be condemned, or even suspected.
1. Bolland. prop. p. 58. 2. Concil. t. 2. p. 1289.
As Priests and Deacons are commanded, by The Celibacy of the

the Seventh Article of this Letter, to abstain from Clergy first
Marriage, and this is the first Opportunity that proposed in the
Council of Elvira.
has offered of mentioning the Celibacy of the
Clergy, a short Digression on such a material Point of Discipline in
the Church may not, perhaps, be unacceptable to the Reader. The
laying of this heavy Burdens on the Shoulders of the Clergy, a
Burden too heavy for most of them to bear, as Experience has
shewn, was first moved in the Council of Elvira, held about the Year

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(Ebook) Cancer Drugs by Judy Matray-devoti ISBN

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Copyright © 2006 by Infobase Publishing

Library of Congress Cataloging-in-Publication Data

Text and cover design by Terry Mallon

Printed in the United States of America

This book is printed on acid-free paper.

1. The Cellular Basis of Cancer 10

5. Hormones and Hormone Antagonists 64

6. Molecularly Targeted Agents 78

7. Biologic Response Modifiers 94

9. The Future 113

Further Reading 125

David J. Triggle, Ph.D.

An in-depth account of drugs and drug discovery can be

CELL STRUCTURES AND THEIR FUNCTIONS

• nucleus—where the cell’s genetic material is stored in the

• mitochondria—these organelles convert nutrients into

• lysosomes—cellular digestive enzymes are found in these

• endoplasmic reticulum—this structure is important to pro-

function of other cells in their environment. Ribosomes are

• microtubules—these are hollow, tubular filaments made

THE CELL CYCLE AND ITS PHASES

Figure 1.1 The cell and its internal structure.

IMPORTANT FEATURES OF TUMOR GROWTH:

1. Normal cells require external growth factors to enter the

Figure 1.2 The cell cycle.

cells live independently of these growth factors, so they

2. Normal cells limit their division when they come into

3. Normal cells eventually die, to be replaced by new ones.

telomere is gone, the cell can no longer divide. Young,

4. The DNA of all cells is constantly exposed to destructive ener-

Each of these characteristics, from the many genetic and

HOW CANCER DRUGS WORK

Targeting cell function and molecular synthesis

Figure 1.3 Dividing cancer cell. Colored transmission elec-

classes of cancer drugs work because their chemical structure

thrown into the gears of a machine, a drug that imperfectly

Altering cell signaling and organization

Affecting cell surface receptors

Changing the cancer cell environment

molecules in the body so that cancer cell receptors do not

THE BEST WAY TO ADMINISTER A CANCER DRUG

HOW DO CANCER DRUGS KNOW TO

Figure 1.4 Chemicals for cancer treatment. © Bernard

to their intended targets, most cancer drugs today are

SARCOMA, LEUKEMIA, MYELOMA,

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