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    Apoptosis and Its Relation To Cancer: Engin Ulukaya (MD, PHD)

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    ZellDinch
    Apoptosis plays a key role in cancer development and treatment. Deregulation of apoptosis allows cancer cells to evade cell death, promoting tumor growth. Determining a patient's apoptosis-related protein levels and tumor response to chemotherapy can help predict treatment outcomes and select the most effective drugs to induce apoptosis in cancer cells. Individualized chemotherapy based on chemosensitivity testing holds promise to improve cancer treatment by excluding ineffective drugs and selecting the most likely to work for each patient.

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    Apoptosis and Its Relation To Cancer: Engin Ulukaya (MD, PHD)

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    ZellDinch
    39 views38 pages
    Apoptosis plays a key role in cancer development and treatment. Deregulation of apoptosis allows cancer cells to evade cell death, promoting tumor growth. Determining a patient's apoptosis-related protein levels and tumor response to chemotherapy can help predict treatment outcomes and select the most effective drugs to induce apoptosis in cancer cells. Individualized chemotherapy based on chemosensitivity testing holds promise to improve cancer treatment by excluding ineffective drugs and selecting the most likely to work for each patient.

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    Apoptosis plays a key role in cancer development and treatment. Deregulation of apoptosis allows cancer cells to evade cell death, promoting tumor growth. Determining a patient's apoptosis-related protein levels and tumor response to chemotherapy can help predict treatment outcomes and select the most effective drugs to induce apoptosis in cancer cells. Individualized chemotherapy based on chemosensitivity testing holds promise to improve cancer treatment by excluding ineffective drugs and selecting the most likely to work for each patient.

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    39 views38 pages

    Apoptosis and Its Relation To Cancer: Engin Ulukaya (MD, PHD)

    Uploaded by

    ZellDinch
    Apoptosis plays a key role in cancer development and treatment. Deregulation of apoptosis allows cancer cells to evade cell death, promoting tumor growth. Determining a patient's apoptosis-related protein levels and tumor response to chemotherapy can help predict treatment outcomes and select the most effective drugs to induce apoptosis in cancer cells. Individualized chemotherapy based on chemosensitivity testing holds promise to improve cancer treatment by excluding ineffective drugs and selecting the most likely to work for each patient.

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    of 38

    APOPTOSIS AND ITS

    RELATION TO CANCER

    Engin ULUKAYA (MD, PhD)

    Uludağ University, Department of Biochemistry, 16059 Bursa / TURKEY


    Talk about....

    1. APOPTOSIS

    2. DEREGULATION OF APOPTOSIS IN
    MALIGNANCIES

    3. POTENTIAL ROLE OF APOPTOSIS


    IN CANCER TREATMENT
    APOPTOSIS
    CellsCells are born,
    are born, live live
    for afor
    given
    periodaofgiven
    time period
    and then die
    of time and then dieBowen, 1998
    Bowen, 1998

    APOPTOSIS
    --- Physiological cell death
    --- Cell suicide
    --- Cell deletion
    --- Programmed cell death
    WHERE can APOPTOSIS be
    ENCOUNTERED ?

    ... Growth of Embrio


    ... Tissue Homeostasis
    ... Immunology
    ... Chronic viral diseases
    ... Neurodegenerative diseases
    ... Reperfusion injury
    ... Insuline-dependent Diabetes
    ... Atheroschlerosis
    ... Miyokard Infarction
    ... AIDS
    ... Development and Treatment of Malignancies
    12000

    10000
    Number of Apoptosis-Relevant

    8000
    Publications

    6000

    4000

    2000

    0
    1984- 1986- 1988- 1990- 1992- 1994- 1996- 1998-
    1985 1987 1989 1991 1993 1995 1997 1999
    Years
    GENERAL FEATURES OF
    APOPTOSIS

    1) A number of activities take place


    ... Occupation of death receptors
    ... Dimerization of Bcl-2 family members
    ... Release of cytochrome c
    ... Activation of caspases
    ... Activation of DNase
    2) Translocation of phosphatidylserine
    3) ATP-dependency
    4) Internucleosomal DNA fragmentation
    (ladder pattern)
    5) No apoptosis at +4 oC
    6) No inflammation
    Calbiochem, Inc

    CELL SURFACE DEATH RECEPTORS


    CASPASES
    Caspase-1 (ICE)
    Caspase-2 (ICH-1, Nedd-2)
    Caspase-3 (CPP32, Apopain, Yama)
    Caspase-4 (ICH-2, TX, ICEreıı)
    Caspase-5 (ICErelııı, TY)
    Caspase-6 (Mch2)
    Caspase-7 (ICE-LAP3, Mch3, CMH-1)
    Caspase-8 (FLICE, Mch5, MACH)
    Caspace-9 (Mch6, ICE-LAP6)
    Caspase-10 (Mch4)
    SUBSTRATES for CASPASES
    ... PARP
    ... DNA-PK
    ... pRb
    ... Lamins
    ... NuMA
    ... Fodrin
    ... -Aktin
    ... Mdm2
    ... Cyclin A2
    ... Presenilin
    ... Others
    THE APOPTOTIC PATHWAY

    Triggers Modulators Effectors Substrates DEATH

    . Growth factor . FADD . Caspases . Many cellular


    Deprivation . TRADD proteins
    . Hypoxia . FLIP . DNA
    . Loss of adhesion . Bcl-2 family
    . Death receptors . Cytochrome c
    . Radiation . p53
    . Chemotherapy . Mdm2
    AN APOPTOTIC CELL IN CULTURE

    Collins JA, et al. 1997


    From the archive of Dr Ulukaya
    DEREGULATION OF
    APOPTOSIS IN
    MALIGNANCIES
    1 Transfection studies in rat fibroblasts

    Apoptosis

    Ras
    Tumor growth

    Apoptosis
    c-myc Tumor growth
    2

    Igney and
    Krammer
    1999
    3
    CASPASES CAN BE INHIBITED BY
    VIRUSES

    ... CrmA
    ... Baculovirüs p35
    ... Ebstein Barr Virüs BHRFI
    proteini
    ... Ebstein Barr Virüs LMP-1 proteini
    4
    APOPTOSIS-RELATED CELLULAR
    PROTEINS INVOLVE IN THE
    PROGRESSION OF MALIGNANCIES
    ... p53
    ... pRb
    ... Fas
    ... Mdm2
    ... c-myc
    ... c-Jun
    ... Bcl-2 family
    Bcl-2 FAMILY
    Anti-apoptotic Pro-apoptotic
    - Bcl-2 - Bax
    - Bcl-XL - Bcl-XS
    - Mcl-1 - Bak
    ******************* - Bad
    - p35 (Baculovirüs) ***************
    -BHRF1 (Ebstein-Barr -????
    Virüsü)
    - LMW5 HL (“African Swine
    Fever Virus”)
    - p19 (E1B) (Adenovirüs)
    Bad Bad
    Bcl-XL Bcl-2

    CELL
    Bcl-XL SURVIVAL
    Bcl-2
    Bax Bax

    Bax Bax

    CELL DEATH
    5 Various Expression Levels of Apoptosis-Related
    Proteins Determine Patient-Specific Malignancy ?

    . Increased Bcl-2 –--------------------------------- Poor prognosis

    . Increased FasL –--------------------- Decreased CTL number

    . FasL induction (with Doxorubicin)----------------Determines


    chemosensitivity

    . Overexpression of Bax---------------- Improve the efficacy of


    chemotherapy

    . p53 antibodies ------------------- Resistance to chemotherapy


    with cisplatin + 5-Fluorouracil
    • "Right now we lump
    patients together and
    treat them with the
    same drugs and then
    deal with their
    variable response to
    treatment. We're
    essentially treating
    different diseases
    with the same
    medicine.”

    • Richard Klausner,
    OncoTech, Inc 1997
    Question 1 ...

    Is Cancer Puzzling ?
    Question 2 ...

    Does Apoptosis Held a Key


    Position in the Treatment of
    Cancer ?
    POTENTIAL ROLE OF APOPTOSIS IN
    CANCER TREATMENT
    Things to do ....

    (1)
    Determination of the Apoptosis-
    Related Proteins
    . p53 gene status--------------- Modulates the
    chemosensitivity

    . p53 level –---------- Predictor for the response to chemo- or


    radiotherapy (Advanced Head and Neck Carcinomas,
    Epithelial Ovarian Ca)

    . Mutant p53 --------- Overall shortened survival (Breast Ca)

    . Ratio of Bcl-2/Bax -----------------------–--- Prognostic factor


    (Hematologic Malignancies, Colon Ca)

    . Bcl-2 alone –-------- Prognostic factor (Advanced Over Ca)


    Things to do ....
    (2)
    Measurement of the Cytotoxic (Apoptosis-
    Inducing) Effects of Chemotherapeutic
    Agents on Individual Cancer Tissue
    Specimens Removed from Cancer Patients
    In Other Words...

    • Designation of Patient-Specific Chemotherapy


    METHODS FOR THE
    CHEMOSENSITIVITY TESTING
    1... Clonogenic assay
    2... Thymidine Incorporation Assay
    3... Tissue Explant Assay
    4... MTT assay
    5... Fluorescence Assay
    6... DISC Assay
    7... The ISCO* ATP-Tumor Chemosensitivity Assay
    (ATP-TCA)

    *ISCO, International Society of Chemosensitivity Testing in Oncology


    From the archive of Dr Ulukaya
    ATP-Tumour Chemosensitivity Assay
    Overnight enzyme
    Tumour dissociation
    1mm3 Fragments

    Incubate for 5-7 days, Wash cells,


    extract ATP and read Plate at 20,000 count and
    in a luminometer cell/well estimate viability

    Kindly supplied from Dr I Cree


    In the literature (1)....

    ... A working tumor chemosensitivity assay (TCA) could be


    of immense benefit to the pharmaceutical industry,
    oncologists and their patients (Cree and Kurbacher, 1997)

    ... ATP-TCA can be used to select patients who might


    benefit from specific chemotherapeutic agents alone or in
    combination (Cree et al, 1999)
    In the literature (2)....
    Chemotherapy guided by the ATP-TCA

    ... Retrospective clinical correlation in breast carcinoma (Cree


    et al, 1996): 97% assay evaluability, 76% accuracy, 27%
    imrovement in clinical response rate

    ... A greater benefit with regard to both ORR and PFS in


    platinum refractory patients (Kurbacher et al, 1998): Overall
    survival, 97 weeks / 69 weeks; Response rate, 64% / 37%
    TWO GREAT BENEFITS

    • Exclusion of chemotherapeutic agents


    which are not likely to be effective, thereby
    avoidance of their potential toxicity

    • Selection of chemotherapeutic agents with


    the greatest likelihood of clinical
    effectiveness for improved response rates and
    prolonged survival
    SUMMARY
    • It is considered that defective apoptosis is a feature of
    malignant development

    • Induction of apoptosis in malignancies is to be aimed

    • Detection of apoptosis-related proteins may be of importance


    in the prediction of patient’s response to chemo- or radio-
    therapy as well as of survival rates

    • Chemosensitivity testing, thereby individualised


    chemotherapy on the basis of patient-specificity, seems to be
    promising in the succesful treatment of malignancies. This
    testing, thereby, may revolutionize the way we use anti-cancer
    drugs in near future

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