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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

APOPTOSIS AND ITS RELATION TO CANCER

Engin ULUKAYA (MD, PhD)

Uludağ University, Department of Biochemistry, 16059 Bursa / TURKEY

talk about
Talk about....

1. APOPTOSIS

2. DEREGULATION OF APOPTOSIS IN MALIGNANCIES

3. POTENTIAL ROLE OF APOPTOSIS IN CANCER TREATMENT

slide4

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
where can apoptosis be encountered
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

general features of apoptosis

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

slide8
2) Translocation of phosphatidylserine

3) ATP-dependency

4) Internucleosomal DNA fragmentation (ladder pattern)

5) No apoptosis at +4 oC

6) No inflammation

slide9

Calbiochem, Inc

CELL SURFACE DEATH RECEPTORS

caspases

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)

slide11

SUBSTRATES for CASPASES

... PARP

... DNA-PK

... pRb

... Lamins

... NuMA

... Fodrin

... -Aktin

... Mdm2

... Cyclin A2

... Presenilin

... Others

slide12

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

slide13

AN APOPTOTIC CELL IN CULTURE

Collins JA, et al. 1997

slide16

1

Transfection studies in rat fibroblasts

Apoptosis

Ras

Tumor growth

Apoptosis

c-myc

Tumor growth

slide17

2

Igney and Krammer1999

caspases can be inhibited by viruses

3

CASPASES CAN BE INHIBITED BY VIRUSES

... CrmA

... Baculovirüs p35

... Ebstein Barr Virüs BHRFI proteini

... Ebstein Barr VirüsLMP-1 proteini

slide19

4

APOPTOSIS-RELATED CELLULAR PROTEINS INVOLVE IN THE PROGRESSION OF MALIGNANCIES

... p53

... pRb

... Fas

... Mdm2

... c-myc

... c-Jun

... Bcl-2 family

slide20

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
  • ***************
  • ????
slide21

Bad

Bad

Bcl-XL

Bcl-2

CELL

SURVIVAL

Bcl-XL

Bcl-2

Bax

Bax

Bax

Bax

CELL DEATH

slide22

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

slide23
"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

slide27

Things to do ....

(1)

Determination of the Apoptosis-Related Proteins

slide28

. 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)

slide29

Things to do ....

(2)

Measurement of the Cytotoxic (Apoptosis-Inducing) Effects of ChemotherapeuticAgents on Individual Cancer Tissue Specimens Removed from Cancer Patients

in other words
In Other Words...
  • Designation of Patient-Specific Chemotherapy
methods for the chemosensitivity testing

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

slide35

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

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

two great benefits

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
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