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Chemical biologicalcarcinogens csbrp
This document discusses various chemical, physical, hormonal, and biological carcinogens and their role in cancer development. It describes how chemicals like benzpyrenes, aflotoxin B1, and polycyclic hydrocarbons can cause DNA damage and initiate cancer through metabolic activation. Physical carcinogens like radiation are also discussed, as well as how viruses like HPV and EBV can integrate into host DNA and induce oncogene expression, leading to cancer. The stages of initiation and promotion in chemical carcinogenesis are summarized.
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Chemical biologicalcarcinogens csbrp
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- 12. Carcinogens • Agents causingcancer (thro’ genetic damage) • Classification • Chemical • Physical • Hormonal • Biological • History: • 18th Century Sir Percival Pott • Scrotal skin cancer in chimney sweepers • Exposure to soot
- 13. 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)
- 14. Initiation • Induction ofmutation 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
- 15. Promotion • Process oftumor 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
- 16. Chemical Carcinogens Initiation andPromotion
- 17. 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
- 18. Concept of initiationand 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
- 19. • The cellularchanges resulting from application of promoters do not affect DNA directly and are reversible
- 20. Property of directacting & 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
- 21. Epoxides • From hydrocarbons •Structure of Cyclic ether • Highly reactive chemicals • Can form adducts with many cellular elements
- 22. 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
- 23. Metabolic action ofcarcinogens • 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
- 24. Metabolic action ofcarcinogens • 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
- 25. Molecular targets ofchemical 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
- 26. Initiated cell • UnrepairedDNA 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
- 27. Chemical Carcinogen -Mechanism • Reactive electrophiles – Electron deficient substances – Binds with electron rich portions of cells (DNA) • Target molecules – DNA – mutation - carcinogenesis • Initiated cell Unrepaired DNA damage One cycle of proliferation Irreversible damage Vulnerable to promotion
- 28. 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
- 29. Promotion of carcinogenesis •Tumor promotion steps- multiple steps. Proliferation of preneoplastic cells Malignant conversion Tumor progression (depends on cells & stroma)
- 30. 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
- 31. Promotion of carcinogenesis •Involved in clonal expansion and aberrant differentiation of initiated cells
- 32. Carcinogenic chemicals • Directacting alkylating agents • Polycyclic aromatic hydrocarbons • Aromatic amines and azo dyes • Naturally occurring carcinogens • Nitrosamines and amides • Miscellaneous agents
- 33. Carcinogenic chemicals Direct actingalkylating 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
- 34. Carcinogenic chemicals Polycyclic aromatichydrocarbons • 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
- 35. Carcinogenic chemicals Aromatic amines& azo dyes • Source: food coloring agents Eg: Butter yellow, Scarlet red • Beta naphthylaimine – rubber industry - bladder cancer
- 36. Carcinogenic chemicals Naturally occurringcarcinogens • Source: moldy grains, peanuts, rice - aspergillus flavus - aflatoxin B1. • Potent hepatocarcinogen • Correlates with increased incidence in china / Africa
- 37. Carcinogenic chemicals Nitrosamines andamides • Source: Nitrostable amines and nitrates used as food preservative - bacteria convert them to nitrites • Induce gastric cancers
- 38. Carcinogenic chemicals miscellaneous 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
- 39. Tests for ChemicalCarcinogenecity • Experimental induction – Animals: Initiator……Promoter • Tests for mutagenicity (Ames Test)
- 40. Ames test • Invitro test for carcinogenicity testing • Ability of potential carcinogens to induce mutations in selected strains of salmonella typhi murium
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- 42. Katsusaburō Yamagiwa was thefirst to prove chemical carcinogenesis Johannes Fibiger Katsusaburō Yamagiwa
- 43. Physical Carcinogens • Radiation •UV rays of sunlight • Ionizing radiation – Medical – Occupational • Non radiation • Mechanical irritation – Stone in the bladder
- 44. Radiation • Mechanism – DNArepair 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
- 45. Hormonal Carcinogens • Contraceptives –Liver adenoma • Anabolic steroids – Hepatic tumors • Estrogen – Breast cancer – Endometrial cancer
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- 47. Biological Carcinogens • OncogenicViruses – 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
- 48. 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
- 49. Viral oncogenesis • Replication •Integration • Oncogene/suppressor gene
- 50. EBV • LMP1-proliferation ofBcells via CD40 • Promotes BCL2-reduced apoptosis • EBNA2-activates cyclinD • Bcells escape immuneregulation due to lack of Ag expression • Acquire myc mutation leading to neoplasm
- 51. Hepatitis B • HBV—leadsto chronic liver cell injury and proliferation • Predisposing to mutations • HBx encoded by HBV acts on NFkB pathway and signal transduction pathways
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- 53. H. pylori Adenocarcinoma Chronic gastritis Atrophy Intestinalmetaplasia Dysplasia Carcinoma Lymphoma Gastritis B cell proliferation Genetic abnormality MALToma
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Editor's Notes
- #24 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.
- #44 Johannes Andreas Grib Fibiger (23 April 1867 – 30 January 1928) was a Danish scientist, physician, and professor of pathological anatomy who won the 1926 Nobel Prize in Physiology or Medicine. Fibiger had claimed to find an organism he called Spiroptera carcinoma that caused cancer in mice and rats. He received a Nobel prize for this discovery. Later, it was shown that this specific organism was not the primary cause of the tumors. Moreover, Katsusaburo Yamagiwa, only two years later in 1915 successfully induced squamous cell carcinoma by painting crude coal tar on the inner surface of rabbits' ears. Yamagiwa's work has become the primary basis for this line of research.[1] Because of this, some consider Fibiger's Nobel Prize to be undeserved particularly because Yamagiwa did not receive the prize.[2] Encyclopædia Britannica's guide to Nobel Prizes in cancer research mentions Yamagiwa's work as a milestone without mentioning Fibiger.