APOPTOSIS AND ITS RELATION TO CANCER Engin ULUKAYA (MD, PhD) Uludağ University, Department of Biochemistry, 16059 Bursa/TURKEYSlide 2
Talk about.... 1. APOPTOSIS 2. DEREGULATION OF APOPTOSIS IN MALIGNANCIES 3. POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENTSlide 3
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 passingSlide 5
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 MalignanciesSlide 7
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 DNaseSlide 8
2) Translocation of phosphatidylserine 3) ATP-reliance 4) Internucleosomal DNA discontinuity (step design) 5) No apoptosis at +4 o C 6) No aggravationSlide 9
Calbiochem, Inc CELL SURFACE DEATH RECEPTORSSlide 10
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)Slide 11
SUBSTRATES for CASPASES ... PARP ... DNA-PK ... pRb ... Lamins ... NuMA ... Fodrin ... - Aktin ... Mdm2 ... Cyclin A2 ... Presenilin ... OthersSlide 12
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 . ChemotherapySlide 13
AN APOPTOTIC CELL IN CULTURE Collins JA, et al. 1997Slide 14
From the chronicle of Dr UlukayaSlide 15
DEREGULATION OF APOPTOSIS IN MALIGNANCIESSlide 16
1 Transfection contemplates in rodent fibroblasts Apoptosis Ras Tumor development Apoptosis c-myc Tumor developmentSlide 17
2 Igney and Krammer1999Slide 18
3 CASPASES CAN BE INHIBITED BY VIRUSES ... CrmA ... Baculovirüs p35 ... Ebstein Barr Virüs BHRFI proteini ... Ebstein Barr V irüs LMP-1 proteiniSlide 19
4 APOPTOSIS-RELATED CELLULAR PROTEINS INVOLVE IN THE PROGRESSION OF MALIGNANCIES ... p53 ... pRb ... Fas ... Mdm2 ... c-myc ... c-Jun ... Bcl-2 familySlide 20
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 *************** ????Slide 21
Bad Bcl-X L Bcl-2 CELL SURVIVAL Bcl-X L Bcl-2 Bax CELL DEATHSlide 22
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-FluorouracilSlide 23
"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, IncSlide 24
Question 1 ... Is Cancer Puzzling ?Slide 25
Question 2 ... Does Apoptosis Held a Key Position in the Treatment of Cancer ?Slide 26
POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENTSlide 27
Things to do .... (1) Determination of the Apoptosis-Related ProteinsSlide 28
. 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)Slide 29
Things to do .... (2) Measurement of the Cytotoxic (Apoptosis-Inducing) Effects of Chemotherapeutic Agents on Individual Cancer Tissue Specimens Removed from Cancer PatientsSlide 30
In Other Words... Assignment of Patient-Specific ChemotherapySlide 31
Chemosensitivity Testing (Onkogram in Turkish)Slide 32
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 OncologySlide 33
From the file of Dr UlukayaSlide 34
Kindly provided from Dr I CreeSlide 35
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)Slide 36
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-TCASlide 37
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 survivalSlide 38
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
World J Gastroenterology. 2006 Nov 28; 12 (44): 7172-7178. Shin Vivian, Wu William, Chu Kent, Wo ...
What are some normal screening tests you can get the opportunity to help avert disease? What are ...
Guys: 3 most regular sorts of growth are prostate, lung and bronchial, colorectal. 3. ... Sort C ...
One in five Americans will create skin tumor throughout a lifetime. ... Somewhere around 40 and ...
Arsenic Emissions (tons/year) of the ENO Power Plant, Slovakia ... Prievidza region versus Slova ...
Otis W. Brawley, M.D. Boss Medical Officer Executive Vice President American Cancer Society . Te ...
Properties of disease cells. Lessened or over the top control of growthbenign tumors additionall ...
Worldwide Cancer Incidence and Mortality. 12.1 million new cases assessed in 2007 (5.4 million i ...
Brachytherapy. CET. Radiation is offered specifically to targetGradient impact
Current Approaches in Metastatic Breast Cancer Edgardo Rivera, MD Chief, Breast Medical Oncolo ...
RTKs and rational cancer therapy. Dr Andrejs Liepins/Science Photo Library. Are we making pr ...
Genes y el ambiente como causales de cáncer Joseph F. Fraumeni, Jr., M.D. Conferencia del Te ...
Nursing Care of the Client with Cancer. Cancer Background A. Definition 1. Family of compl ...
CANCER DE PULMON. Instituto Nacional de Enfermedades Respiratorias. CANCER DE PULMON. EPI ...
Endometrial Cancer. Faina Linkov, PhD Research Assistant Professor University of Pittsburgh ...
OCTUBRE MES CONTRA EL CANCER DE MAMA. En México cada año mueren más de tres mil 500 mujer ...