biochemistry of cancer ,an overview
TRANSCRIPT
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Dr. Subodhini Abhang
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Cell that is transformed .
Recognized by population of abnormal cells within the
normal tissue causing destruction of normal cell
population & behave like parasite.
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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
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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.
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Causes of cancer
• Physical
• Chemical
• Biological
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Effects of radiation
UV Rays X Rays Gama Rays
Mutagenic & Carcinogenic
Damage to DNA.Pyrimidine dimers to formFormation of apurinic or apyrimidinic sites.Single & double strand break & cross linkingFree radical formation.( OH ͘ , super oxide)
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Effects of radiation
Pyrimidine dimers
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Chemical carcinogens
• 80% of cancer caused by chemicals
• Organic eg. benzo pyrine,
• Organic eg. benzo pyrine,
• chemicals
dimethylnitrosamine
Inorganic eg. Cadmium , Arsenic
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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
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Role of initiator & promoter
Initiator Carcinogenbenzopyrene
PromotorCroton oil
Potential tumor cellsProliferating cancer cells
Release & migration of cancer cells
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Promotors
Promotor
• Cyclomates
• saccharin
• Metabolites of Tyrosine :
Phenol & cresol
Tryptophan: Indol & Indol
acetate
Tissue
• Tumor of Bladder
• Tumor of Gastrointestinal tract.
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Mechanism of action of chemical carcinogen
Pro -carcinogen proximate carcinogen
ultimate carcinogen
(highly reactive)
Electrophiles (deficient in electrons)
Enzyme responsible for activation-----Cytochrome P450
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Some chemical carcinogens
Class• Polycyclic aromatic
hydrocarbons.
• Azo dyes (Aromatic amines)
• Nitrosamines
• Various drugs ( alkylating & acetylating agents)
• Aflatoxins(fungus AspergillusFlavus)
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.
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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
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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
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Mechanism of infective retrovirus formation
C DNA or provirus
Retrovirus
Reverse transcriptase
Cell
Viral DNA
1.
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Host DNA
Becomes a part of host DNA
1a.Process of integration of viral genes into cellular DNA
Viral DNA
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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:
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myc
myc
LTR LTR
provirus
2. Enhancer Insertion
Myc mRNA
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3. Translocation
Chromosome 4
Chromosome 4
Chromosome 20
Chromosome 20
Before After
In chronic granulocytic leukemia: Translocation between 9th and 22nd chromosome.
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Break
Break
Gene for H –Chains
myc gene
myc gene
Burkitt’s Lymphoma: chromosomal translocation
8 8 8
14 14 14
Heavy chainsOf immunoglobulin
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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.
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5. Single point mutation
V-ras oncogene --------murine retrovirus
polypeptide related to G protein
modulates the activityadenylate cyclase
role in cellular responses of hormones & drugsC- 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
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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.
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Tumor suppressor genes OrAntioncogenes
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
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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 EnzymesHormones
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Tumor markers.
Marker Associated cancer(s)
Oncofetal antigens
carcinoembryonic antigen(CEA)------------Colon, Stomach, Breast, Lung and Pancreasalpha fetoprotein (AFP) ------------Liver and germ cells of testisCancer antigen ( CA 125) ------------Ovarian cancer of epithelial origin.Prostate specific antigen ------------Prostate cancer
HormonsCalcitonin ------------CA of medullary thyroidCatecholamines and their metabolites (VMA) -------------Neuroblastoma
EnzymesProsthetic acid phosphatase ------------ Prostate cancerNeuron specific enolase ------------NeuroblastomaAlkaline phosphatase(ALP) ------------Bone secondary's
Specific ProteinsImmunoglobulin ----------- multiple myeloma
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