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APOPTOSIS AND ITS RELATION TO CANCER

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.

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APOPTOSIS AND ITS RELATION TO CANCER

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  1. APOPTOSIS AND ITS RELATION TO CANCER Engin ULUKAYA (MD, PhD) Uludağ University, Department of Biochemistry, 16059 Bursa / TURKEY

  2. Talk about.... 1. APOPTOSIS 2. DEREGULATION OF APOPTOSIS IN MALIGNANCIES 3. POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENT

  3. APOPTOSIS

  4. Cells are born, live for a given period of time and then die Bowen, 1998 Cells are born, live for a given period of time and then die Bowen, 1998 APOPTOSIS • --- Physiological cell death • -- Cell suicide • -- Cell deletion • -- Programmed cell death

  5. 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

  6. 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

  7. 2) Translocation of phosphatidylserine 3) ATP-dependency 4) Internucleosomal DNA fragmentation (ladder pattern) 5) No apoptosis at +4 oC 6) No inflammation

  8. Calbiochem, Inc CELL SURFACE DEATH RECEPTORS

  9. 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)

  10. SUBSTRATES for CASPASES ... PARP ... DNA-PK ... pRb ... Lamins ... NuMA ... Fodrin ... -Aktin ... Mdm2 ... Cyclin A2 ... Presenilin ... Others

  11. THE APOPTOTIC PATHWAY Triggers Modulators Effectors Substrates DEATH . Many cellular proteins . DNA . FADD . TRADD . FLIP . Bcl-2 family . Cytochrome c . p53 . Mdm2 . Caspases . Growth factor Deprivation . Hypoxia . Loss of adhesion . Death receptors . Radiation . Chemotherapy

  12. AN APOPTOTIC CELL IN CULTURE Collins JA, et al. 1997

  13. From the archive of Dr Ulukaya

  14. DEREGULATION OF APOPTOSIS IN MALIGNANCIES

  15. 1 Transfection studies in rat fibroblasts Apoptosis Ras Tumor growth Apoptosis c-myc Tumor growth

  16. 2 Igney and Krammer1999

  17. 3 CASPASES CAN BE INHIBITED BY VIRUSES ... CrmA ... Baculovirüs p35 ... Ebstein Barr Virüs BHRFI proteini ... Ebstein Barr VirüsLMP-1 proteini

  18. 4 APOPTOSIS-RELATED CELLULAR PROTEINS INVOLVE IN THE PROGRESSION OF MALIGNANCIES ... p53 ... pRb ... Fas ... Mdm2 ... c-myc ... c-Jun ... Bcl-2 family

  19. Bcl-2 FAMILY Anti-apoptotic • -Bcl-2 • Bcl-XL • Mcl-1 • ******************* • p35 (Baculovirüs) • BHRF1 (Ebstein-Barr Virüsü) • LMW5 HL (“African Swine Fever Virus”) • p19 (E1B) (Adenovirüs) Pro-apoptotic • - Bax • - Bcl-XS • Bak • Bad • *************** • ????

  20. Bad Bad Bcl-XL Bcl-2 CELL SURVIVAL Bcl-XL Bcl-2 Bax Bax Bax Bax CELL DEATH

  21. 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

  22. "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, 1997 OncoTech, Inc

  23. Question 1 ... Is Cancer Puzzling ?

  24. Question 2 ... Does Apoptosis Held a Key Position in the Treatment of Cancer ?

  25. POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENT

  26. Things to do .... (1) Determination of the Apoptosis-Related Proteins

  27. . 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)

  28. Things to do .... (2) Measurement of the Cytotoxic (Apoptosis-Inducing) Effects of ChemotherapeuticAgents on Individual Cancer Tissue Specimens Removed from Cancer Patients

  29. In Other Words... • Designation of Patient-Specific Chemotherapy

  30. Chemosensitivity Testing (Onkogram in Turkish)

  31. 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

  32. From the archive of Dr Ulukaya

  33. Kindly supplied from Dr I Cree

  34. 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)

  35. In the literature (2).... ... 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% Chemotherapy guided by the ATP-TCA

  36. 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

  37. 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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