chemical biologicalcarcinogens csbrp
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Bladder Carcinoma
Benzidine
Tobacco leavesBenzpyrenes
Cycasin
Aflotoxin B1
Polycyclic hydrocarbons
Polycyclic hydrocarbons
Percival PottScrotal cancer
Chemical CarcinogensBiological Carcinogens
Dr.CSBR.Prasad, M.D.,
Carcinogens• Agents causing cancer (thro’ genetic damage)
• Classification• Chemical• Physical• Hormonal• Biological
• History:• 18th Century Sir Percival Pott • Scrotal skin cancer in chimney sweepers• Exposure to soot
Chemical Carcinogen
• Synthetic • Naturally occurring• Directly acting (no metabolic activity)
• Indirectly acting (procarcinogens, needs metabolic activity)
• Initiators (irreversible DNA damage)
• Promoters (reversible non DNA damage)
Initiation
• Induction of mutation in genome of cells• Initiated cells are not transformed cells• They have no growth autonomy/unique
phenotype• In contrast to normal cells, can give rise to
tumors when appropriately stimulated by promoting agents
Promotion
• Process of tumor induction in a previously initiated cell by chemicals.
• The effect of promoters is short lived and reversible
• They do not affect DNA• Non tumorigenic by themselves
Chemical CarcinogensInitiation and Promotion
Major Chemical Carcinogens• Direct-Acting Carcinogens
– Alkylating Agents • Anticancer drugs (cyclophosphamide , chlorambucil , nitrosoureas) • β-Propiolactone, Dimethyl sulfate, Diepoxybutane
– Acylating Agents • 1-Acetyl-imidazole, 2-Dimethylcarbamyl chloride
• Procarcinogens That Require Metabolic Activation – Polycyclic and Heterocyclic Aromatic Hydrocarbons
• Benz(a)anthracene, Benzo(a)pyrene, Dibenz(a,h)anthracene, • 3-Methylcholanthrene, 7,12-Dimethylbenz(a)anthracene
– Aromatic Amines, Amides, Azo Dyes • 2-Naphthylamine (β-naphthylamine), Benzidine, 2-Acetylaminofluorene,
Dimethylaminoazobenzene (butter yellow)– Natural Plant and Microbial Products
• Aflatoxin B1, Griseofulvin, Cycasin, Safrole, Betel nuts
• Others • Nitrosamine and amides, Vinyl chloride, nickel, chromium, Insecticides,
fungicides, Polychlorinated biphenyls
Concept of initiation and promotion sequence
• Initiation - exposure of cells to sufficient dose of carcinogen
• Potenial to induce tumor• Initiation alone is insufficient• Permanent DNA damage- mutation.• Rapid and irreversible• Promoters can induce tumor in an initiated
cell, by themselves are not tumorigenic
i
• The cellular changes resulting from application of promoters do not affect DNA directly and are reversible
Property of direct acting & ultimate carcinogens
• Highly reactive electrophiles (electron deficient) react with nucleophilic (electron rich) sites in the cell
• Non enzymatic reactions - covalent adducts b/n carcinogen & nucleotide DNA
• Electron rich sites in cell:– DNA– RNA– Proteins
Epoxides
• From hydrocarbons• Structure of Cyclic ether• Highly reactive chemicals• Can form adducts with many cellular
elements
Adducts
• An adduct (from the Latin adductus, "drawn toward") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components
• Covalent adducts: can damage DNA, RNA and proteins
Metabolic action of carcinogens
• Most carcinogens need activation to form ultimate carcinogens
• Other metabolic pathways detoxify • Carcinogenic potency
– Inherent reactivity of electrophilic derivative– Balance b/n metabolic activation and
inactivation
Metabolic action of carcinogens
• Carcinogenesis is regulated in part by polymorphism in the genes that encode the genes
• Age, sex and nutritional status determine the internal dose of toxicants
Molecular targets of chemical carcinogens
• Mutations affecting oncogenes, tumor suppressor genes and genes that regulate apoptosis and genes involved in DNA repair
• DNA is the primary target• No single or unique alteration with initiation• Each class of carcinogen produces limited pattern
of DNA damage• Each carcinogen produces molecular ‘fingerprint’
that links specific chemical with their mutational effect
Initiated cell
• Unrepaired DNA alterations are essential first step in initiating tumor
• Damaged DNA template must replicate to be inheritable and permanent
• Quiescent cells may never be affected by carcinogens, unless mitogenically stimulated
• Concurrent exposure to viruses, parasites, hormones induce proliferation
Chemical Carcinogen - Mechanism
• Reactive electrophiles– Electron deficient substances– Binds with electron rich portions of cells (DNA)
• Target molecules– DNA – mutation - carcinogenesis
• Initiated cellUnrepaired DNA damage
One cycle of proliferation
Irreversible damage
Vulnerable to promotion
Promotion of Carcinogenesis
• Phenols, artificial sweeteners
• No sudden change• Need sufficient time and dose• Changes reversible• Enhance the effect of carcinogens• Acts through growth factor pathway
Promotion of carcinogenesis
• Tumor promotion steps- multiple steps. Proliferation of preneoplastic cells Malignant conversion Tumor progression (depends on cells &
stroma)
Promotion of carcinogenesis
• The effect of promoters are pleiotropic• Induction of cell proliferation is a sine qua
none phenomenon of promoters• They act via signal transduction pathways
ex.,protein kinase C,• Activation of PKC - series of
phosphorylations- cell proliferation and differentiation
Promotion of carcinogenesis
• Involved in clonal expansion and aberrant differentiation of initiated cells
Carcinogenic chemicals
• Direct acting alkylating agents• Polycyclic aromatic hydrocarbons• Aromatic amines and azo dyes• Naturally occurring carcinogens• Nitrosamines and amides• Miscellaneous agents
Carcinogenic chemicals Direct acting alkylating agents
• Activation dependent, weak carcinogens• Used as anticancer drugs• Induce lymphoid neoplasms, leukemia etc.,• Powerful immunosuppressive agents• Eg: Cyclophosphamide, Busulfan• Interact with DNA and damage
Carcinogenic chemicalsPolycyclic aromatic hydrocarbons
• Source: Combustion of smoke, smoked meat, animal fat processing broiled meat, smoked fish
• Induce lung and bladder cancer• Most potent carcinogens known• Require metabolic activation• Skin paint - skin cancer• Subcutaneous injection - sarcoma
Carcinogenic chemicalsAromatic amines & azo dyes
• Source: food coloring agents Eg: Butter yellow, Scarlet red• Beta naphthylaimine – rubber industry -
bladder cancer
Carcinogenic chemicalsNaturally occurring carcinogens
• Source: moldy grains, peanuts, rice - aspergillus flavus - aflatoxin B1.
• Potent hepatocarcinogen• Correlates with increased incidence in china
/ Africa
Carcinogenic chemicalsNitrosamines and amides
• Source: Nitrostable amines and nitrates used as food preservative - bacteria convert them to nitrites
• Induce gastric cancers
Carcinogenic chemicalsmiscellaneous agents
• Asbestos - Bronchogenic ca. Mesothelioma,GI cancers
• Asbestos + smoking = many fold risk ca lung• Vinyl chloride - hemangiosarcoma liver• Chromiun & nickle - Ca lung - volatile
industrial environment pollutant• Arsenic – skin cancer• Hormones –endometrial cancer
Tests for Chemical Carcinogenecity
• Experimental induction– Animals: Initiator……Promoter
• Tests for mutagenicity (Ames Test)
Ames test
• In vitro test for carcinogenicity testing• Ability of potential carcinogens to induce
mutations in selected strains of salmonella typhi murium
Ames test
Katsusaburō Yamagiwawas the first to prove chemical carcinogenesis
Johannes Fibiger Katsusaburō Yamagiwa
Physical Carcinogens
• Radiation• UV rays of sunlight• Ionizing radiation
– Medical– Occupational
• Non radiation• Mechanical irritation
– Stone in the bladder
Radiation
• Mechanism– DNA repair by formation of
pyrimidine dimers• Normally taken care by
nucleotide excision repair (NER) – Recognition of DNA repair– Incision of strands on both sides
of damage– Removal of damages
nucleotides– Synthesis of nucleotide patch– Ligation
– Mutation in oncogenes & suppressor genes
Hormonal Carcinogens
• Contraceptives– Liver adenoma
• Anabolic steroids– Hepatic tumors
• Estrogen– Breast cancer– Endometrial cancer
Biological Carcinogens
Biological Carcinogens• Oncogenic Viruses
– DNA• Human Papilloma Virus Papilloma, Ca. of cervix, skin• EB virus Lymphoma, Nasopharyngeal carcinoma• HHV 8 Kaposi sarcoma, B cell lymphoma• Hepatitis B Hepatocellular carcinoma• Pox virus Molluscum contagiosum, Papilloma
– RNA• HTLV 1 Adult T cell Leukemia/Lymphoma• HTLV 2 T cell variant of Hairy cell leukemia• Hepatitis C Hepatocellular carcinoma
• Oncogenic Bacteria• H. pylori Gastric lymphoma, Adenocarcinoma
Human papilloma virus
• HPV- 6,11-genital warts• HPV-16,18- invasive squamous cell ca• Early viral genes E6&E7 are oncogeneic• E7 binds to Rb and displaces E2F• E6 inactivates TP53,degrades BAX
Viral oncogenesis
• Replication• Integration• Oncogene/suppressor
gene
EBV
• LMP1-proliferation of Bcells via CD40• Promotes BCL2-reduced apoptosis• EBNA2-activates cyclinD• Bcells escape immuneregulation due to lack
of Ag expression• Acquire myc mutation leading to neoplasm
Hepatitis B
• HBV—leads to chronic liver cell injury and proliferation
• Predisposing to mutations• HBx encoded by HBV acts on NFkB
pathway and signal transduction pathways
Viral oncogenesis
H. pylori
Adenocarcinoma Chronic gastritis
AtrophyIntestinal metaplasiaDysplasiaCarcinoma
LymphomaGastritisB cell proliferationGenetic abnormalityMALToma
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