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Biochemistry of cancer

Biochemistry of cancer. Dr.S.Chakravarty. Burkitt Lymphoma. Biomedical importance second most common cause for death world wide Humans of all the ages affected and wide variety of organs are affected. Introduction. Cancer cells are characterized by four properties

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Biochemistry of cancer

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  1. Biochemistry of cancer Dr.S.Chakravarty Burkitt Lymphoma

  2. Biomedical importance • second most common cause for death world wide • Humans of all the ages affected and wide variety of organs are affected

  3. Introduction Cancer cells are characterized by four properties • Unrestrained control of growth • Immortality • Invasion of local tissues • Metastasis

  4. Carcinogens • Radiant energy- UV rays, X- rays, and γ-rays ■ Pyrimidinedimers ■ DNA cross linking ■ Free radical generation • Chemical agents- 80% of cancers is caused by the chemicals Exposure can occur during • occupation • Diet • Life style – cigarette smoking, tobacco ,alcohol • Other ways ( therapeutic drugs may be carcinogenic)

  5. Chemical carcinogens

  6. Chemical carcinogens • Structure :- no common structure, both organic and inorganic compounds can be cause cancer • Action :- • Directly carcinogenic :- mechlorethamine, beta –propriolactone • Some are procarcinogens :- Need metabolic activation procarcinogen→ proximate carcinogen→ ultimate carcinogen

  7. Mechanism of chemical carcinogenesis • procarcinogen→ proximate carcinogen→ ultimate carcinogen • 2- acetylaminofluorine Sulfate ester of N- OH-AAF • Bind covalently to macromolecules including DNA, RNA and proteins • Carcinogens are electrophiles ( deficient in electrons) readily attack nucleophilic groups of DNA

  8. Mutagenecity – can be checked by Ames test- Salmonella typhimurium( his–ve ) Salmonella typhimurium( his+ve ) Chemical carcinogen

  9. Initiation and promotion Initiator (Benzopyrene) NO TUMORS Initiator (Benzopyrene) Initiator (Benzopyrene) Promoter (Croton Oil) TUMORS Initiator (Benzopyrene) Promoter (Croton Oil) NO TUMORS TIME

  10. A variety of compounds like Phenobarbital and saccharin can act as promoters • The active agent of croton oil is a mixture of phorbol esters

  11. USMLE ! Oncogenic viruses • Oncogenic viruses contain either DNA or RNA as their genome. • Integration of viral genes in to the host DNA- overrules the regulatory checks and balances of the cellular mechanism- transformation

  12. Oncogenes play a crucial role in carcinogenes • Oncogenes are the genes capable causing cancer • Michel bishop and Harold Varmus-demonstrated oncogene in Rous sarcoma virus • The same sequences are also present in humans- cellular oncogenes designated by prefix ‘c’ and viral oncogene as ‘v’ eg, c- src and v- src. • A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. • > 100 protooncogenes are present in humans

  13. Proto-oncogenesare regulatory genes • Products of many oncogenes are polypeptide growth factors e.g. sis gene produces PDGF • Or Act as receptors for growth factors e.g. erb-B produces receptor for EGF. • Some act on key intracellular pathways e.g. src product tyrosine kinase enzyme phosphorylatestyr residue-activation of intracellular events.

  14. USMLE ! Cellular oncogenes

  15. Protooncogenes are activated to oncogenes by various mechanisms Five mechanisms have been described • Promoter insertion • Enhancer insertion • Chromosomal translocation • Gene amplification • Point mutation

  16. Promoter insertion • Insertion of viral c DNA near the oncogene acts as a promoter A. B. PROVIRUS LTR LTR myc myc ………… …………. Inactive mycmRNA

  17. ENHANCER insertion • Insertion of viral c DNA down stream of the oncogene. A. B. PROVIRUS LTR LTR myc myc ………… ………… myc mRNA Inactive Important :- mycacts as a DNA binding protein and alters gene expression

  18. USMLE ! Gene translocation Reciprocal translocation in Burkitt’s lymphoma Translocation is from short arm of chromosome 8 to short arm of chromosome 14 Translocated piece from chrom. 8 contains myc gene which is placed next to gene transcribing H chain of immunoglobulin and itself become activated

  19. Chr 14 (From Chr 8 )

  20. Important translocations for USMLE USMLE !

  21. USMLE !

  22. USMLE ! Gene amplification • Amplification of genes causing increased expression in to many folds. • Amplification of certain genes are found in some tumours. • Can be induced by certain anticancer drugs which causes drug resistance • Eg, treatment with methotrexate Can be seen as increased homogenously staining regions or as minichromosomes(double minute chr) lacking centromeres

  23. USMLE ! Point mutation • Point mutation is observed in some cancer c-ras c-ras P 21(MUTATION AT 12TH POSITION) P 21 Loss of GTPase activity GTP ase activity Diminishes the activity Of adenylcyclase Overstimulation of adenylcyclase

  24. Polypeptide growth factors are mitogenic • Growth factors are polypeptide substances secreted from different cells which causes mitosis. • Growth factors may be • Endocrine • Paracrine • Autocrine Growth factors acts on mitosis via transmembrane signal transduction

  25. Growth factors

  26. Growth factors cont.,

  27. Growth factors and oncogenes interact in several ways • The products of several oncogene act as growth factors or receptors for growth factors • v-sis codes 100 a.a acids for B chain of PDGF • v-erb codes for truncated receptor V with much of the external domain of the receptor deleted but protein tyrosine kinase activity retained which causes continuous activation.

  28. USMLE ! A number of genes increase susceptibility to cancers

  29. Tumor suppressor genes • Genes which prevents the causation of cancer • These sometimes called as recessive oncogenes or anti oncogenes

  30. USMLE ! Important oncosupressor genes

  31. RB 1 GENE IMPORTANT PROPERTIES • Gene is located on chrom. 13q14 • Familial retinoblastoma occurs after identical mutations in both the alleles • pRB binds certain viral proteins and forms inactive complexes • pRB binds to certain transription factors that are active in S phase thus slowing cell cycle

  32. Properties of p53 gene • Gene is located on the chrom. No 17 • Product is a nuclear phosphoprotein • It binds to specific DNA sequences • It acts as a transcriptional regulator • It binds to various viral proteins forming inactive oligomeric complexes • Mutations in p53 gene are the most common genetic alteration in cancer and are frequent in colon, breast and lung cancer

  33. Biochemical changes in fast growing tumor cells • Increased activity of ribonucleotidereductase • Increased synthesis of RNA and DNA • Decreased pyrimidine catabolism • Increased rates of glycolysis( both aerobic and anaerobic ) • Alterations of isoenzyme patterns , often to a fetal pattern • Synthesis of fetal proteins • Inappropriate synthesis of growth factors • Telomerase

  34. Tumor markers These are the substances released by the cancer cells and detectable in blood useful for the following purposes • Diagnosis of cancer • Follow up of cancer and to monitor effectiveness of therapy. • Prognosis

  35. USMLE ! common tumor markers

  36. Alpha fetoprotein • Chemical nature : is a oncofetal protein • Sources: in embryonic life mainly produced by liver and yolk sac • Clinical use: • Diagnosis: of hepatocellular cancer and germ cell tumor (testicular carcinoma). • Prognosis: if AFP > 10µg/L and bilirubin > 2mg/dl indicates bad prognosis. • Monitoring of therapy

  37. Carcinoembyonic antigen • Chemical nature: it is a glycoprotein • Sources: present in fetal gastrointestinal tract • Clinical use: • Diagnosis of adenocarcinoma of colon and levels are increased in smokers and aged people • Main use is monitoring of the colon cancer • CEAmay also be raised in 10-15% of breast cancer

  38. Prostate specific antigen • Chemical nature: it is a extracellular protease • Source : prostate gland • Normal serum levels: it is usually present in serum either in free form or complex with anti protease ( alpha-2 macroglobulin). Normal serum level- 0 to 0.4 µg/L in 40 – 70 years of age • Clinical use: • PSA + per rectal examination is used for screening the prostate cancer in 50-75 years of age group

  39. Human chorionic gonadotropin • Chemical nature: is a glycoprotein • Source:trophoblastic tissues of placenta and testes • Normal serum levels : < 5 IU/L • Clinical use: • markedly elevated in choriocardcinoma and germ cell tumors • Mainly used as diagnostic, therapeutic and prognostic tool for germ cell tumors

  40. Metastasis Neoplastic cells GF ANGIOGENESIS COLLGENASES Degradation of basement membrane ANGIOGENESIS Interaction with ECM Degradation of ECM Invasion of blood vessels

  41. DNA DAMAGING AGENTS NORMAL CELLS DNA DAMAGE MUTATION ON GENOME OF SOMATIC CELLS TELOMERASE ACTIVATION OF ONCOGENES ALTERATION OF GENES THAT REGULATE APOPTOSIS INACTIVATION OF SUPPRESSOR GENES EXPRESSION OF ALTERED GENE PRODUCTS INCREASED SURVIVAL CLONAL EXPANSION OF ALTERED CELLS MALIGNANT NEOPLASM

  42. VHL chr 3

  43. t14:18 ,Burkitt’s Lymphoma, bcl 2

  44. Thank you

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