Download - Cancer biochemistry
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CANCER
DR ROHINI C SANEPROFESSOR
DEPARTMENT OF BIOCHEMISTRY DR D Y PATIL MEDICAL COLLEGE
EBENE
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CANCER• CANCER DISEASE- IN WHICH CELL GROW ABNORMALLY –MALIGNANT NEOPLASM
• (NEW GROWTH )-NEOPLASIA
• A MASS OF TISSUE ---ABNORMAL ,EXCESSIVE,UNCORDINATED ,PURPOSELESS PROLIFERATION
• ONCOLOGY = ONCOS ( TUMOR ) + LOGY (STUDY )
• BENIGN TUMOR---THAT DOSE NOT INVADE /SPREAD –NON CANCEREROUS
• MALIGNANT TUMOR /CANCER –INVADES DESTROY TISSUE IN WHICH ORIGINATES –CAN SPREAD IN OTHER TISSUES VIA BLOOD STREAM & LYMPHATIC SYSTEM
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PROPERTIES OF CANCER CELLS
• UNRESTRAINED GROWTH
• INVANSION OF LOCAL TISSUE
• METASTASIS
MORPHOLOGICAL CHANGES
SHAPE ---ROUNDER
MOTILITY ---LOSS OF CONTACT INHIBITION OF MOVEMENTS
GROWTH --- LOSS OF CONTACT INHIBITION –MULTILAYER /NUMBER OF NUCLEI
BIOCHEMICAL CHANGES
ALTERED GENE REGULATION ---DNA SYNTHESIS ---RNA SYNTHESIS ---PROTEIN SYNTHESIS---ANABOLISM---GROWTH
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BIOCHEMICAL CHANGESALTERED GENE REGULATION
INCREASED DNA SYNTHESIS
INCREASED RNA SYNTHESIS
INCREASED PROTEIN SYNTHESIS
ANABOLISM---GROWTH FACTORS &HORMONES
INCREASED AEROBIC & ANAEROBIC GLYCOLYSIS
SYNTHESIS OF LACTIC ACID & LACTIC ACIDOSIS
ALTERATION OF CELL SURFACE DUE CHANGES IN COMPOSITION OF GLYCOPROTEINS & GLYCOSPHINGOLIPIDS
DECREASED
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BIOCHEMICAL CHANGES
• CARCINOMAS –CANCER ARISES FROM EPITHELIAL TISSUE
• SARCOMAS –MESENCHYMAL TISSUE
• LEUKAEMIAS-WBC
• LYMPHOMAS
• HEPATOMAS –HEPATOCYTES
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ETIOLOGYFAMILIAL GENETIC FACTOR
GEOGRAPHIC FACTORS
• ASIANS-NASOPHARYNGEAL
• JAPNESE –BREAST
• AFRICA –SKIN
• EUROPEANS--COLON
• ENVRIMENTAL FACTORS
• AGE->50YRS
• SEX-MEN >WOMEN
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ENVIROMENTAL FACOTRS
• CIGARETTE SMOKING
• ALCOHOL ABUSE
• TOBACCO
• BETEL NUT
• ARSENIC
• VINYL CHLORIDE
• ASBESTOS
• BENZENE
• NAPHTHYLOMINE
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PHYSICAL CARCINOGENS• RADIENT ENERGY ---UV LIGHT ,IONIZING RADIATIONS
• EXAMPLS –SUNLIGHT ,WELDERS ARC ,UV LAMPS ---SKIN CANCER
• FORMATION OF PYRIMIDINE DIMER IN DNA STRAND
• FORMATION OF APURINIC OR APYRIMIDINE SITE ELIMINATION OF BASES
• BREAKING OF CROSS LINKING OF SINGLE OR DOUBLE STRAND OF DNA
IONIZING RADIATIONS –X RAYS ,ALPHA ,BETA ,GAMMA RAYS ,RADIOACTIVE ISOTOPES ,PROTONS ,NEUTRONS
• IONIZING RADIATIONS---DAMAGE DNA ,DISLODGE IONS FROM H2O& BIOMOLECULES ,INTERACT WITH PROTEINS, DNA-----CANCER (MUTAGENESIS)
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HORMONAL CARCINOGENESIS
• HORMONE SENSITIVE TISSUE ---BREAST ,ENDOMETRIUM, MYOMETRIUM,VAGINA THYROID, ,LIVER ,PROSTRATE,TESTIES
• ESTROGENS---OVARIAN,ENDOMETRIUM CARCINOMA
• CONTRACEPTIVE HORMONES ---BREAST CANCER
• ANABOLIC STEROIDS---ATHLETS,LIVER CANCER
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Biological carcinogens • Viruses, parasites ,bacteria
DNA VIRUS
• PAPOVIRUS ---HPV (HUMAN PAPILLOMA VIRUS),SV40B,POLYOMA VIRUS
• HERPES VIRUS –EPSTEIN BAR VIRUS
• ADENOVIRUS –12,18,31
• HEPITITIS B VIRUS (HBV)
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RNA VIRUS
ACUTE TRANSFORMING VIRUS :ROUS SARCOMA VIRUS :LEUKEMIA VIRUS
SLOW TRANSFORMING :MOUSE MAMMARY TUMOR VIRUS
HUMAN T CELL LYMPHOTROPIC VIRUS --- HTLV -1,HTLV II
RNA REVERSE TRANSCRIPATASE
RNA –DNA NEOPLASIA
NOT ALL RETROVIRUSES ARE CARCINOGENIC
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CARCINOGENESIS &CHEMICAL CARCINOGENS
INITIATORSDIRECT –DO NOT REQUIRE METABOLIC ACTIVATIONEXAMPLES ---ALKYLATING AGENTS—CYCLOPHOSPAHMIDE
ACYLATING AGENTS-- NITROSOUREA
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CARCINOGENESIS & CHEMICAL CARCINOGENS
INDIRECT –AROMATIC HYDROCARBONS---BENZOPYRENES
TOBACO
COAL TAR
SMOKE
AROMATIC AMINES AZO DYES BETA NAPHTHYL AMINE
ACETALAMINO FLUORENE
NATURALLY OCCURING ALF TOXIN
BETEL NUT
MISCELLENEOUS ----- VINYL CHLORIDE ,ASBESTOS ,NI, CARBON MONOXIDE
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PROMOTERS OF CARCINOGENS
• NOT CARCINOGENS BUT INITIATE CARCINOGENESIS
• EXAMPLES –PHENOLS,ESTROGENS,ARTIFICIAL SWEETNER SACCHARINE,CYCLAMATES
• METABOLIC ACTIVATION
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Pro-carcinogens
Proximate carcinogens
Ultimate carcinogens
(free radicals)
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Mechanism of action of chemical carcinogens
DIRECT REACTING CARCINOGEN (WITH NO METABOLIC ACTIVATION )&INDIRECT (WITH METABOLIC ACTIVATION FORMS REACTIVE ELECTROPHILES
Electrophiles (free radicals)—deficient in electrons
Interact with DNA Neutrophiles (chiefly DNA,RNA,PROTEINS)
DAMAGE (DNA MUTATION ,DNA repair enzymes fail)
Neoplastic transformation
Development of cancer
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Apoptosis• Dropping /falling of the normal programmed destruction of cells
.,during embryogenesis, development of adult life.
• Destruction of apoptosis promote inappropriate cell division ,cell survival ---development of cancer
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Proto-oncogenes –normal genes –stimulate cell divisionProto-oncogenes (activated by physical, chemical, biological carcinogens )-----oncogenes ---growth factor ,growth factor receptors ,signal transduction proteins Tumor suppressor gene –inhibit cell divisionNormal cell –balanced activity of tumor suppressor & protooncogene activator genes ---normal growth & repairNeoplasia –uncontrol cell division ---(1)decreased suppressor activity (2)increased proto-oncogene activity
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Oncogene expressionproto –oncogenes control normal growth &cell division
Mutated versions of proto-oncogenes act as oncogenes
examples
• Growth factors
• Growth factor receptors
• Protein involved in signal transduction(protein kinase that phosphorylates tyrosine /serine residue )---GTP binding protein
• Proteins involved in signaling gene expression in nucleus
• some growth factor induce growth but not cell division –cell grows large in size without ever dividing
• 50 types of growth factors identified –first platelet diving growth factor (PDGF)
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Mechanisms of activation of proto-oncogenes to oncogenes
• Promoter and enhancer insertion
• Chromosomal translocation
• Gene amplification
• Point mutation
• Effect of oncogene on growth ---putting one foot on accelerator of automobile
• Tumor suppressor gene ---taking one foot from the break
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ONCOGENES CHROMOSOMES VIRUS ONCOGENE PRODUCTS
abl 9 Abbleson leukemia in mouse
Tyrosine kinase
erb B 7 Erythroblastosis in chicken Receptor for E & PR
erb –A 17 Erythroblastosis in chicken Transforming growth factor receptors
myc 08 Myelocytoma in chicken Platelet derived growth factor
ras 12 Rat sarcoma GTPase
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ONCOSUPPRESSOR ABBREVATIONS CHROMOSOMES
RETINOBLASTOMA RB 13
FAMILLIAL BREAST CANCER
BRCA1BRCA2
17
GENE FOR PROTEIN 53 P53 17
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Retinoblastoma gene RB gene
• Nucleo phosphoprotein –regulates DNA SYNTHESIS
• SWITCH OF CELL PROLIFERATION—SUPPRESS TUMOR FORMATION
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MODE OF DNA VIRAL ONCOGENESIS VIRUS + DNA
ALTERATION IN GENE EXPRESSION
CELL TRANSFORMATION
TYPE OF PROTEIN ALTERED
INACTIVATION OF TUMOR SUPPRESSOR
NEOPLASM
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MODE OF RNA VIRAL ONCOGENESIS
RNA
DNA (SINGLE STANDED )
C DNA (DOUBLE STRANDED)
C DNA GETS INCORPORATED IN HOST DNA ---PROTEINS /ENZYMES ,
HORMONES SYNTHESIZED
NEOPLASTIC CHANGES
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IMMUNOLOGIC SURVEILLANCE• IMMUNE SYSTEM
• RECOGNIZES SPECIFIC ANTIGENS
• DESTROY CANCER CELLS CARRYING ANTIGENS ---STOP ABNORMAL GROWTH
• IF IMMUNOLOGIC SURVELLIENCE FAILS CANCER GROWS
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Tumor markers• DEFINITION –BIOLOGICAL SUBSTANCES SYNTHESIZED OR RELEASED
BY CANCER CELLS AND FOUND IN INCREASED AMOUNT IN BLOOD ,BODY FLUID OR TISSUES INDICATING PRESENCE OF CANCER
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APPLICATIONS OF TUMOR MARKERS• DIAGNOSIS (SCREENING )
• DIFFENTIAL DIAGNOSIS
• STAGING OF CANCER
• DETECTION OF RECURRENCE
• MONITORING RESPOSE TO THERAPY (PROGNOSIS)
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Tumor markers
ENZYMESPROSTATIC ACID PHOSPHATASE---PROSTRATE CANCER
ALKALINE PHOSPHATASE --- BONE SECONDARIES
PROTEINS
• PROSTRATE SPECIFIC ANTIGEN----PSA--PROSTRATE CANCER
• MULTIPLE MYELOMA----SERUM PROTEIN IMMUNOGLOBULIN/BENCE JONES PROTEINS
• C PEPTIDE ---INSULINOMA
• BETA MICROGLOBULINS –BETA CELL LYMPHOMAS
CARBOHYDRATE
• CARBOHYDRATE ANTIGEN (CA—125)—OVARIAN ,ENDOMETRIUM
• CARBOHYDRATE ANTIGEN (CA—549)—BREAST ,OVARIAN
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Tumor markers
HORMONES & THEIR METABOLITE
• Beta HCG ---CHORION CARCINOMA
• CALCITONIN ---MEDULARYCARCINOMA
• VANILLYL MANDELLIC ACID –NEUROBLASTOMA
• PROLACTIN –PITUITARY ADENOMA
• PTH –RENAL,BREAST,LIVER
ONCOFETAL ANTIGENS
• ALPHA FETO PROTEINS ---(AFP) HEPATOMA
• CARCINOEMBRYONIC ANTIGEN---(CEA)--COLON ,LUNG ,GIT
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CANCER & DIET • INCREASED ANIMAL FAT
• INCREASED BACTERIAL FLORA
• CONVERSION OF ACIDS & STEROLS
• CARCINOGENS
• BENEFIAL ROLE OF VITAMIN C ,E ,SELENIUM ,BETA CAROTENE
• TRACE ELEMENTS ---Manganese ,zinc ,selenium, copper
• Tomatto ,cabbage ,cauliflower
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Cancer therapy• Chronic myeloid leukaemia (CML)
• ONCOGENES C—abl (9 ) ,bcr (22)---protein kinase ,tyrosine kinase
• Trnlocation of bcr gene to abl gene --bcr –abl gene –protein kinase enzyme
• Bcl---abl not regulated
• Increased protein kinase
• Gleevec ---antitumor drug ---STI 571 USED IN TREATMENT OF BCR-ABL GENE—(tyrosine KINASE) ---90% cancer patients respond to treatment –rapid growth decreased but side effects
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MONCLONAL ANTIBODIES
TARGET USED AGAINST CANCER
Ritutab CD20 ON B CELLS BETA CELL LEUKEMIA
HERCEPTIN HER 2/EGFR 2 BREAST CANCER
BERACIZUMAB VGEF COLORECTAL CANCER
NILITINIB TYROSINE KINASE SOLID CANCER
IMATINIB TYROSINE KINASE NON SMALL CELL LUNG CANCER
GENTFITINIB TYROSINE KINASE CML
PANITUMUMAB EGFR COLORECTAL CANCER
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