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Malignancy. The division of ordinary cells is correctly controlled. New cells are shaped for development or to supplant dead ones.Cancerous cells partition over and over wild despite the fact that they are not required, they group out other ordinary cells and capacity anomalous. They can likewise demolish the right working of real organs..
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APOPTOSIS AND ITS RELATION TO CANCER Engin ULUKAYA (MD, PhD) Uludağ University, Department of Biochemistry, 16059 Bursa/TURKEY

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

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APOPTOSIS

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Cells are conceived, live for a given timeframe and after that kick the bucket Bowen, 1998 Cells are conceived, live for a given timeframe and afterward bite the dust Bowen, 1998 APOPTOSIS - Physiological cell demise - Cell suicide - Cell cancellation - Programmed cell passing

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WHERE can APOPTOSIS be ENCOUNTERED ? ... Development of Embrio ... Tissue Homeostasis ... Immunology ... Unending viral ailments ... Neurodegenerative maladies ... Reperfusion damage ... Insuline-subordinate Diabetes ... Atheroschlerosis ... Miyokard Infarction ... Helps ... Advancement and Treatment of Malignancies

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GENERAL FEATURES OF APOPTOSIS 1) various exercises occur ... Control of death receptors ... Dimerization of Bcl-2 relatives ... Arrival of cytochrome c ... Enactment of caspases ... Initiation of DNase

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2) Translocation of phosphatidylserine 3) ATP-reliance 4) Internucleosomal DNA discontinuity (step design) 5) No apoptosis at +4 o C 6) No aggravation

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Calbiochem, Inc CELL SURFACE DEATH RECEPTORS

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CASPASES Caspase-1 (ICE) Caspase-2 (ICH-1, Nedd-2) Caspase-3 (CPP32, Apopain, Yama) Caspase-4 (ICH-2, TX, ICEre ıı ) Caspase-5 (ICErel ııı , TY) Caspase-6 (Mch2) Caspase-7 (ICE-LAP3, Mch3, CMH-1) Caspase-8 (FLICE, Mch5, MACH) Caspace-9 (Mch6, ICE-LAP6) Caspase-10 (Mch4)

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

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THE APOPTOTIC PATHWAY Triggers Modulators Effectors Substrates DEATH . Numerous cell proteins . DNA . FADD . TRADD . FLIP . Bcl-2 family . Cytochrome c . p53 . Mdm2 . Caspases . Development figure Deprivation . Hypoxia . Loss of attachment . Demise receptors . Radiation . Chemotherapy

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

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From the chronicle of Dr Ulukaya

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DEREGULATION OF APOPTOSIS IN MALIGNANCIES

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1 Transfection contemplates in rodent fibroblasts Apoptosis Ras Tumor development Apoptosis c-myc Tumor development

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2 Igney and Krammer1999

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3 CASPASES CAN BE INHIBITED BY VIRUSES ... CrmA ... Baculovirüs p35 ... Ebstein Barr Virüs BHRFI proteini ... Ebstein Barr V irüs LMP-1 proteini

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

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Bcl-2 FAMILY Anti-apoptotic - Bcl-2 Bcl-X L Mcl-1 ******************* p35 (Baculovirüs) BHRF1 (Ebstein-Barr Virüsü) LMW5 HL ("African Swine Fever Virus") p19 (E1B) (Adenovirüs) Pro-apoptotic - Bax - Bcl-X S Bak Bad *************** ????

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Bad Bcl-X L Bcl-2 CELL SURVIVAL Bcl-X L Bcl-2 Bax CELL DEATH

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5 Various Expression Levels of Apoptosis-Related Proteins Determine Patient-Specific Malignancy ? . Expanded Bcl-2 – - - Poor forecast . Expanded FasL – - - Decreased CTL number . FasL acceptance (with Doxorubicin)- - Determines chemosensitivity . Overexpression of Bax - Improve the viability of chemotherapy . p53 antibodies - - Resistance to chemotherapy with cisplatin + 5-Fluorouracil

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"Right now we knot patients together and treat them with similar medications and after that arrangement with their variable reaction to treatment. We\'re basically treating diverse maladies with a similar solution." Richard Klausner, 1997 OncoTech, Inc

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Question 1 ... Is Cancer Puzzling ?

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

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POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENT

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

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. p53 quality status - Modulates the chemosensitivity . p53 level – - Predictor for the reaction to chemo-or radiotherapy (Advanced Head and Neck Carcinomas, Epithelial Ovarian Ca) . Mutant p53 - Overall abbreviated survival (Breast Ca) . Proportion of Bcl-2/Bax - - – - Prognostic variable (Hematologic Malignancies, Colon Ca) . Bcl-2 alone – - Prognostic element (Advanced Over Ca)

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

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In Other Words... Assignment of Patient-Specific Chemotherapy

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Chemosensitivity Testing (Onkogram in Turkish)

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METHODS FOR THE CHEMOSENSITIVITY TESTING 1... Clonogenic test 2... Thymidine Incorporation Assay 3... Tissue Explant Assay 4... MTT examine 5... Fluorescence Assay 6... Circle Assay 7... The ISCO* ATP-Tumor Chemosensitivity Assay (ATP-TCA) *ISCO, International Society of Chemosensitivity Testing in Oncology

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From the file of Dr Ulukaya

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Kindly provided from Dr I Cree

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In the writing (1).... ... A working tumor chemosensitivity examine (TCA) could be of enormous advantage to the pharmaceutical business, oncologists and their patients (Cree and Kurbacher, 1997) ... ATP-TCA can be utilized to choose patients who may profit by particular chemotherapeutic specialists alone or in blend (Cree et al, 1999)

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In the writing (2).... ... Review clinical relationship in bosom carcinoma (Cree et al, 1996) : 97% test evaluability, 76% precision, 27% imrovement in clinical reaction rate ... A more prominent advantage as to both ORR and PFS in platinum stubborn patients (Kurbacher et al, 1998 ): Overall survival, 97 weeks/69 weeks; Response rate, 64%/37% Chemotherapy guided by the ATP-TCA

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TWO GREAT BENEFITS Exclusion of chemotherapeutic specialists which are not prone to be successful , subsequently shirking of their potential lethality Selection of chemotherapeutic operators with the best probability of clinical viability for enhanced reaction rates and delayed survival

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SUMMARY It is viewed as that imperfect apoptosis is a component of harmful improvement Induction of apoptosis in malignancies is to be pointed Detection of apoptosis-related proteins might be of significance in the forecast of patient\'s reaction to chemo-or radio-treatment and additionally of survival rates Chemosensitivity testing, consequently individualized chemotherapy on the premise of patient-specificity, is by all accounts promising in the succesful treatment of malignancies. This testing, subsequently, may alter the way we utilize against malignancy medicates in not so distant future

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