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Biochemistry of cancer

Biochemistry of cancer BY Dr. Subodhini Abhang

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Biochemistry of cancer

  1. 1. Dr. Subodhini Abhang
  2. 2.  Cell that is transformed . Recognized by population of abnormal cells within the normal tissue causing destruction of normal cell population & behave like parasite.
  3. 3. A simplified hypothesis for development of cancer Inactive anti-oncogenes Diminish regulation by apoptosis gene Oncogenic Mutations viruses Environmental factors( physical and chemical) Oncogene Activation Carcinogenesis
  4. 4. Characteristics of differentiated cell  Lack contact inhibition .  Trap for nitrogen compounds.  Site of growth.  Loss of control on cell division.  Decreased protein degradation as compared to synthesis.  Transfer modified characters to daughter cells & subsequent progeny.  Loss of anchorage.
  5. 5. Causes of cancer • Physical • Chemical • Biological
  6. 6. Effects of radiation UV Rays X Rays Gama Rays Mutagenic & Carcinogenic Damage to DNA. Pyrimidine dimers to form Formation of apurinic or apyrimidinic sites. Single & double strand break & cross linking Free radical formation.( OH ͘ , super oxide)
  7. 7. Effects of radiation Pyrimidine dimers
  8. 8. Chemical carcinogens • 80% of cancer caused by chemicals • Organic eg. benzo pyrine, • Organic eg. benzo pyrine, • chemicals dimethylnitrosamine Inorganic eg. Cadmium , Arsenic
  9. 9. How carcinogens enter in the body ? Occupation ==== Asbestos, benzene Diet --------------- Aflatoxin produced by fungus (Aspergillus flavous) contamination with peanuts. Drugs-------------- Diethylstilbestrol Life style-----------Cigarette smoking Two types ---- Direct  Procarcinogens
  10. 10. Role of initiator & promoter Initiator Carcinogen benzopyrene Promotor Croton oil Potential tumor cells Proliferating cancer cells Release & migration of cancer cells
  11. 11. Promotors Promotor • Cyclomates • saccharin • Metabolites of Tyrosine : Phenol & cresol Tryptophan: Indol & Indol acetate Tissue • Tumor of Bladder • Tumor of Gastrointestinal tract.
  12. 12. Mechanism of action of chemical carcinogen Pro -carcinogen proximate carcinogen ultimate carcinogen (highly reactive) Electrophiles (deficient in electrons) Enzyme responsible for activation-----Cytochrome P450
  13. 13. Some chemical carcinogens Class • Polycyclic aromatic hydrocarbons. • Azo dyes (Aromatic amines) • Nitrosamines • Various drugs ( alkylating & acetylating agents) • Aflatoxins(fungus Aspergillus Flavus) Compound • Benzo pyrene present in cigarette smoke. • An aniline azo dye Used in rubber industry: ca.bladder. • Synthesized in gut from ingested nitrites or derived from digested proteins: gastric cancer • Stilbesterol. • Mold.-- potent hepatic carcinogen.
  14. 14. Oncogenes Genes of viral origin which causes transformation of target cell. Rous 1911 ------ got Nobel prize in 1966 Sarcoma virus DNA RNA –mostly of retroviruses
  15. 15. Oncogenes play a crucial role in carcinogenesis Oncogenes of Rous sarcoma virus: gag pol env src gag: Codes for group specific antigen Pol: Reverse transcriptase Env: certain glycoprotein of viral envelop Src: protein tyrosine kinase
  16. 16. Mechanism of infective retrovirus formation C DNA or provirus Retrovirus Reverse transcriptase Cell Viral DNA 1.
  17. 17. Host DNA Becomes a part of host DNA 1a. Process of integration of viral genes into cellular DNA Viral DNA
  18. 18. Mechanism by which proto-oncogene become oncogene Proto-oncogene is the normal non mutated cellular analog of oncogene. 1. LTR myc myc LTR Provirus Myc mRNA e.g. Avian leukemia virus Promotor insertion:
  19. 19. myc myc LTR LTR provirus 2. Enhancer Insertion Myc mRNA
  20. 20. 3. Translocation Chromosome 4 Chromosome 4 Chromosome 20 Chromosome 20 Before After In chronic granulocytic leukemia: Translocation between 9th and 22nd chromosome.
  21. 21. Break Break Gene for H –Chains myc gene myc gene Burkitt’s Lymphoma: chromosomal translocation 8 8 8 14 14 14 Heavy chains Of immunoglobulin
  22. 22. 5. Gene amplification:  Observed in many tumors.  e.g . Methotrexate administration : leukemia  Inhibitor of dihydrofolate reductase  Dihydrofolate Tetra hydrofolate - ---- required for sythesis of purines & thymine  Tumor cells become resistant to this drug Gene for dihydrofolate reductase becomes amplified resulting in 400 fold increase in activity.
  23. 23. 5. Single point mutation V-ras oncogene --------murine retrovirus polypeptide related to G protein modulates the activity adenylate cyclase role in cellular responses of hormones & drugs C- ras oncogene -------DNA sequencing of C-ras protooncogene Normal human bladder cells cancer of human bladder cells Substitution of amino acid in 12 or 61 position results in GTPase Chronic stimulation on adenylate cyclase
  24. 24. Mechanism of action of oncogenes: 1. Autocrine mechanism--- oncogene product is growth factor* * Over stimulation 2. Oncogene alters the receptor---- receptor is permanently turn on without growth factor binding. 3. Transducer alteration: Transduction –change in genetic make up of a cell by transfer of viral DNA to cell. Change in GTPase stimulatory protein Permanently turn on results in uncoupling of normal ligand receptor binding.
  25. 25. Tumor suppressor genes Or Antioncogenes  Protect an individual from getting cancer.  Deletion removes the growth control of cells and Believed to be a key factor in the development of tumor. P⁵³ ----Absent in most tumors RB gene ( retinoblastoma gene) located in chromosome 13 DCC gene--- Ca colon
  26. 26. Tumor markers. The biochemical indicators employed to detect the presence of cancer are collectively referred to as tumor markers. - Abnormally produced molecules by tumor cells . Eg. Surface antigens cytoplasmic proteins Enzymes Hormones
  27. 27. Tumor markers. Marker Associated cancer(s) Oncofetal antigens carcinoembryonic antigen(CEA)------------Colon, Stomach, Breast, Lung and Pancreas alpha fetoprotein (AFP) ------------Liver and germ cells of testis Cancer antigen ( CA 125) ------------Ovarian cancer of epithelial origin. Prostate specific antigen ------------Prostate cancer Hormons Calcitonin ------------CA of medullary thyroid Catecholamines and their metabolites (VMA) -------------Neuroblastoma Enzymes Prosthetic acid phosphatase ------------ Prostate cancer Neuron specific enolase ------------Neuroblastoma Alkaline phosphatase(ALP) ------------Bone secondary's Specific Proteins Immunoglobulin ----------- multiple myeloma