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Biochemistry of cancer
 

Biochemistry of cancer

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    Biochemistry of cancer Biochemistry of cancer Presentation Transcript

    • 1
    • Cancer cells are characterized by three properties Unrestrained control of growth Immortal Invasion of local tissues MetastasisBiomedical importance second most common cause for death world wide Humans of all the ages affected and wide variety of organs are affected 2
    •  Radiant energy- UV rays, X- rays, and γ-rays ■ Pyrimidine dimers ■ DNA cross linking ■ Free radical generation Chemical agents-80% of the cancer is caused by the chemicalsExposure can occur during occupation Diet Life style – cigarette smoking, tobacco ,alcohol Other ways ( therapeutic drugs may be carcinogenic) 3
    • class compoundPolycyclic aromatic hydrocarbon Benzopyrene, dimethyl benzanthraceneAromatic amines Acetyl aminofluorene, amino benzeneNitrosamines Dimethyl and diethyl nitrosaminesDrugs cyclophosphamideNaturally occurring compounds Aflatoxin B1, dactinomycinInorganic compounds Arsenic, asbestose, beryllium, cadmium, chromium 4
    •  procarcinogen→ proximate carcinogen→ ultimate carcinogen Bind covalently to macromolecules including DNA, RNA and proteins Carcinogens are electrophiles ( deficient in electrons) readily attack nucleophilic groups of DNA 5
    •  Mutagenesity – can be diagnosed byAmes test- Salmonella typhimurium( his–ve ) Chemical carcinogen Salmonella typhimurium( his+ve ) 6
    •  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- transformationVirus Abbreviation Associated cancerEpstein barr virus EBV Burkitt’s lymphoma Nasopharyngeal carcinomaHuman papilloma virus HpV Uterine, cervical caHepatitis B virus HBV hepatoma 7
    •  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. These are also called as protooncogenes. > 100 protooncogenes are present in humans 8
    •  Products of many oncogenes are polypeptide growth factors e.g. sis gene produces PDGF 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 phosphorylates tyr residue-activation of intracellular events. 9
    • oncogene Chromoso Virus carrying Oncogene Subcellular me no. the gene product localization of oncogene product abl 9 Abelson leukemia Tyrosine Plasma membrane virus in mouse kinase Erb-B 7 Erythroblastosis Receptor for membrane virus in chicken EGF Erb-A 17 do Receptor for nucleus TGF myc 8 Myelocytoma DNA binding nucleus virus in chicken protein sis 22 Simian sarcoma PDGF membrane virus in monkeys src 20 Rous sarcoma Tyrosine membrane virus in chicken kinase ras 12 Rat sarcoma virus GTPase cytoplasm 10
    • Five mechanisms has been described Promoter insertion Enhancer insertion Chromosomal translocation Gene amplification Point mutation 11
    •  Insertionof viral c DNA near the oncogene acts as a promoter PROVIRUSA. B. LTR LTR myc myc ………… …………. Myc mRNA 12
    •  Insertion of viral c DNA down stream of the oncogene. PROVIRUSA. B. myc LTR LTR myc ………… ………… Myc mRNA 13
    • Reciprocal translocation in Burkitt’s lymphoma Translocation is from short arm of chromosome 8 to short arm of chromosome 14 and in reverse process translocation occures from short arm of chrom. 14 to chrom. 8Translocated piece from chrom. 8 contains myc gene which is placed next to gene transcribing H chain of immunoglobulin and itself become activated 14
    •  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 15
    •  Point mutation is observed in some cancer c-ras c-ras P 21(MUTATION AT 12TH POSITION) P 21 GTP ase activity Loss of GTPase activityDiminishes the activity Overstimulation of adenyl cyclaseOf adenyl cyclase 16
    •  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 17
    • Growth factors Source FunctionEGF Mouse salivary Stimulates growth of many epidermal and gland epithelial cellsErythropoietin Kidney, urine Development of early erythropoietic cellsIGF-1 and IGF-2 Serum So4 incorporation into cartilage, mitogenic for chondrocytes and exert insulin like effects on many cellsTransforming Tumor cells, Similar to EGFgrowth factor-a placentaTGF-b Placenta, Inhibition of fibroblasts plateletsPlatelet platelets Accelerated wound healingderived growthfactorNerve growth Submaxillary Growth of sensory neuronsfactor gland 18
    • Growth factors Source FunctionGranulocyte Endothelial cells and Stimulatesmacrophage colony T-cells granulocytes,stimulating factor monocytes, megakaryocytesGranulocyte colony Endothelial cells and Stimulatesstimulating factor fibroblasts granulocytesMonocyte colony Endothelial cells Stimulates monocytesstimulating factorTumour necrosis monocyte Necrosis of tumourfactor- alpha(TNF-α ) cells, proliferation of leukocytes 19
    •  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 for EGF which causes continuous activation. 20
    •  Genes which prevents the causation of cancer  These sometimes called as recessive oncogenes or anti oncogenesOncogenes Tumour suppressor genesMutation in one of the allele is Mutation in both the alleles issufficient requiredGain of function of a protein that Loss of function of a proteinsignals cell divisionMutation in somatic cells which is not Mutation in germ cells which isinherited InheritedSome tissue preference Strong tissue preference 21
    • Oncosupressor gene Abbreviation Chromosome no.Retinoblastoma RB 13Wilm’s tumour WT 11Familial adenomatous FAP 5polyposisDeleted in colon cancer DCC 18Gene for protein-53 p53 17Familial breast cancer BRAC 3Von hippel lindau gene VHL 3 22
    • Cytokinesis:The Cell Cycle division of Mitosis: cytoplasm division of M-phase Daughter cells the nucleus G2-phase Cells divide G1-phase Prep. for division: Cell growth + organelles normal cell duplicate activities Synthesis of DNA (chromosomes replicate) Interphase = S-phase G1, S, G2 23
    • RB 1 GENEIMPORTANT PROPERTIES Gene is located on chrom. 13q14 Familial retinoblastoma occurs after identical mutations in both the alleles Product of RB( pRB) gene is a phosphoprotein p RB binds certain viral proteins and forms inactive complexes pRB binds to certain transription factors that are active in S phase thus slowing cell cycle 24
    • 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 25
    • These are the substances released by the cancer cells and detectable in blooduseful for the following purposes Diagnosis of cancer Follow up of cancer and to monitor effectiveness of therapy. Prognosis 26
    • common tumor markersName Increased inAlfa fetoprotein Hepatoma, germ cell tumorsCarcinoembryonic antigen Colorectal, gastrointestinal and lung cancerBeta HCG choriocarcinomaProstate specific antigen Prostrate cancercalcitonin Medullary carcinoma of thyroidCA-125 Overian cancerAlkaline phosphatase Bone secondariesNeuronal specific enolase Nervous system cancerVenyl mandelic acid pheochromacytomaHydroxy indole acetic acid Carcinoid syndrome 27
    •  Chemical nature : is a oncofetal protein Sources: in embryonic life mainly produced by liver and yolk sac Normal serum levels: <10µg/L 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 28
    •  Chemical nature: it is a glycoprotein Sources: present in fetal gastrointestinal tract Clinical use:A. Diagnosis of adenocarcinoma of colon and levels are increased in smokers and aged peopleB. Main use is monitoring of the colon cancerC. CEA may also be raised in 10-15% of breast cancer 29
    •  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 along with the digital examination is used for screening the prostate cancer in 50- 75 years of age group 30
    •  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 31
    •  Chemical nature: polypeptide containing 32 a.a Source: secreted from parafollicular cells of thyroid in response to hypercalcemia Normal serum level: 8.8 ng/L Clinical uses: very useful for screening and diagnosis of medullary carcinoma of thyroid gland Also used to assess severity and monitoring the therapy It is also increased in breast, liver and lung cancers 32