CARCINOGENESIS (basic introduction to carcinogenesis)
- 2. FUNDAMENTAL PRINCIPLES The Heart of carcinogenesis is non- Lethal genetic damage. Genetic damage (mutation) may be due to environmental factors; oChemicals oRadiation oViruses oor may be inherited in germ line Some mutations may be spontaneous
- 3. Tumors is formed by clonal expansion of a single precussor cells with mutation The Principle target for of genetic damage leading to tumours are four classes of genes. These genes are normal regulatory genes; Growth promoting protooncogenes Growth- Inhibiting tumor suppress or genes. Gene that regulate programmed cell death (apoptosis) Gene involved in DNA Repair
- 4. CARCINOGENEC AGENTS AND THEIR INTERRACTION WITH CELLULAR ALTERATION A Number of agents can cause genetic damage and induce neoplastic transformation of cells; Chemical carcinogens Radiant energy Oncogenic Viruses and other Microbes.
- 5. CHEMICAL CARCINOGENESIS Sir Percival pott We owe him the awareness if potential carcinogenicity of chemical agents. In 18th Century related increase incidence of scrotal skin cancer. Noted increase in chimney sweep and related it to chromic exposure to soot. Few year later Danis chimney sweep ruled that members much bathe daily. Result- One of Public measure that was successful in controlling a form of Cancer.
- 6. Since then may chemical carcinogens have been indentified. Ranges from- polycyclic aromatic hydrocarbons Synthetic products Natural occuring (plans and microorganisms Medical drugs etc. STEPS INVOLVED IN CHEMICAL CARANOGENESIS Carcinogenesis is a multistep process Has initiation-promotion sequence
- 7. INITIATION Results from exposure of cells to sufficient dose of carcinogenic agent(initiator). Initiated cell is altered, i.e potential capable of giving rise to tumor. Initiation alone, however is not enough for tumor formation. Initiation causes permanent DNA damage ( mutation) It Rapid and Irreversible and has “Memory” Memory-Tumor can result even as it the application of promoter is delayed for several months after a single application of initiator.
- 8. Promoters can induce tumors in initiated cells By themselves are non-tumorgenic Tumor do not result when promoting agent is applied before, rather than after initiation Promoter not affect DNA. Enhances proliferation of initiated cells. INITIATION OF CHEMICAL CARCINOGENESIS Chemical that initiate carcinogenesis are diverse. Fall in two categories;
- 9. A) DIRECT-ACTING COMPOUNDS Do not require metabolic conversion to be carcinogenic B) INDIRECT-ACTING(PROCARCINOGENS) Requires metabolic conversion in vivo to be ultimate carcinogens Most direct-acting and ultimate carcinogens have one property in common, Are highly reactive electrophiles (electron- deficient atoms) Can react with neucleophilic (electron- rich)site in the cell
- 10. can produce lethal damage But; for carcinogenesis to occur the reaction is nonlethal damage to DNA most chemical carcinogens require metabolic conversion. CARCINOGENIC AGENTS DIRECT ACTING Do not require metabolic conversion in vivo Are weak carcinogens
- 11. Many therapeutic agent fall in the group hence their importance. Cyclophosphamide Chlorambucil Bisulfan Mephalan All are anti-cancer drugs and some also used in treatment of other immunologic disorders Have been documented to induce cancer.
- 12. POLYCLIC AROMATIC HYDROCARBONS Requires metabolic conversion Are most potent carcinogen known. Sources, fossil fuels, combustion of tobacco, animal fats (smoked meat/fish) AROMATIC AMINES AND AZO DYES Carcinogenicity mainly manifested in lung(Metabolism- ultimate carcinogen). People working with analine dyes Rubber industries.
- 13. Some Azo dyes were developed for food colouring Naturally occurring carcinogens produced by plants and Microorganisms EXAMPLES: Aflatoxin B1(Aspergillus flavus) hepatocarcinogen. Other miscellaneous agents includes nitrosamine and amines plus very many other chemicals.