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Cancer 111


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Cancer 111

  1. 1. Neoplasia Aetiology
  2. 2. Aetiology
  3. 3. <ul><li>Introduction </li></ul><ul><li>Development and progression of malignancies is a multi-step process involving number of genetic changes over a period of time as a result of continuous exposure to chemical physical viral or any other carcinogenic agent. </li></ul>
  4. 4. Risk factors for a cancer <ul><li>Age </li></ul><ul><li>Genetic factors. </li></ul><ul><li>Geographical </li></ul><ul><li>Racial factors </li></ul><ul><li>Environmental factors. </li></ul>
  5. 5. <ul><li>The possible causative agents of carcinogenesis </li></ul><ul><li>Chemical carcinogens </li></ul><ul><li>Physical carcinogens </li></ul><ul><li>Viruses </li></ul><ul><li>Hereditary factors </li></ul><ul><li>Hormones </li></ul><ul><li>Cancers associated with chronic diseases </li></ul>
  6. 6. Physical agents <ul><li>Ionizing radiation: </li></ul><ul><li>UV radiation </li></ul>
  7. 7. What happens when exposed <ul><li>Radiation causes its effect by transferring energy to the substance through which it passes </li></ul><ul><li>Result may be: </li></ul><ul><li>Ionization </li></ul><ul><li>Change in the energy state of the electrons or charged molecules. </li></ul>
  8. 8. <ul><li>Physical agents </li></ul><ul><li>Ionizing radiation: </li></ul><ul><li>X rays ,  ,  and  rays </li></ul><ul><li>These agents injure the cells through which it pass by dislodging ions from water and other molecules– Formation of free radicals. </li></ul><ul><li>React with DNA nucleic acids, proteins,and other molecules. </li></ul><ul><li>DNA damages may be; </li></ul><ul><li>Point mutation (Changes in single bases) Breaks in the DNA double strand (wrong reunion) </li></ul>
  9. 9. <ul><li>Lethal doses - Immediate cell death </li></ul><ul><li>Sub lethal doses - Permanent damage in DNA. Malignant transformation. </li></ul><ul><li>Effect of the radiation on different tissues depends on the </li></ul><ul><li>Nature of the tissues (Bone) </li></ul><ul><li>Type of radiation (Determined the depth of penetration) </li></ul>
  10. 10. Evidence to show effects of ionized radiation <ul><li>Nuclear weapons testing; Radio strontium </li></ul><ul><li>Hiroshima and Nagasaki (1945) - leukaemias & other cancers </li></ul><ul><li>Dial painters (Osteosarcomas). </li></ul><ul><li>Radiologists </li></ul>
  11. 11. UV light: <ul><li>Farmers with fair skin who have no melanin protection. (Solar keratosis) </li></ul><ul><li>lip cancers, </li></ul><ul><li>Squamous cell carcinomas </li></ul><ul><li>Basel cell carcinomas </li></ul><ul><li>Malignant melanomas </li></ul><ul><li>Mechanism; Dimmer formation between bases E.g.:Thymidine bases in the DNA. </li></ul><ul><li>(Dimer causes mutation in DNA replication) </li></ul><ul><li>Xeroderma Pigmentosum: </li></ul><ul><li>Lack of enzyme involved in the repair mechanism of damaged DNA. </li></ul>
  12. 12. Hormones <ul><li>Relationship between neoplasia and hormones is complex. </li></ul>
  13. 13. <ul><li>Animal experiments to show hormonal involvement in carcinogenesis: </li></ul><ul><li>Mice: </li></ul><ul><li>High cancer strains oestregen Breast cancers Low cancer strains oestregen Hyperplasia </li></ul><ul><li>Mice or rats. </li></ul><ul><li>Two ovaries were removed and one implanted in the spleen to stop the feed back inhibition of pituitary. (result is occasional ovarian tumours) </li></ul><ul><li>Mice or rats </li></ul><ul><li>Low I, diet and thiouracil </li></ul><ul><li>Reduce thyroxin formation (no feed back effect) </li></ul><ul><li>Result is thyroid hyperplasia/ademoma/carcinomas </li></ul>
  14. 14. <ul><li>However evidence of hormonal involvement in human tumours are rare. But association of hormones in tumours in man have been shown </li></ul><ul><li>Granular cell OESTROGEN tumour of the ovary Endometrial Endometrial hyperplasia Carcinoma </li></ul><ul><li>Artificial sex Oestrogen Enlargement of change Breast Carcinoma Hyperplasia </li></ul>
  15. 15. <ul><li>Hormone dependency ; </li></ul><ul><li>Even though the role of hormones in the aetiology of tumours is not clear, it is clear that hormones are important in maintaining of some tumours. Administration Progress the growth Deprival Regress the tumour eg; prostate </li></ul><ul><li>30% Breast tumours, are hormone dependent </li></ul><ul><li>Later hormonal dependent Independent. </li></ul>
  16. 16. Hereditary predisposition ; <ul><li>Cancer of the breast </li></ul><ul><li>Cancer families </li></ul><ul><li>Hereditary diseases; </li></ul><ul><li>Polyposis coli: Autosomal dominant </li></ul><ul><li>Retinoblastoma </li></ul><ul><li>Xeroderma pigmentation </li></ul>
  17. 17. <ul><li>Virus and cancer </li></ul><ul><li>Ellerman and Band (1908) </li></ul><ul><li>Chicken Cell free extract Erythroid leukaemia </li></ul>
  18. 18. <ul><li>Rous (1911) </li></ul><ul><li>Chicken Cell free extract Sarcoma of sarcoma </li></ul><ul><li>Bittner(1936): </li></ul><ul><li>Foster mothers from cancer free strains New bone mice with cancer susceptible strains </li></ul><ul><li>New bone mice from cancer free strains </li></ul><ul><li>Foster mothers from cancer strains </li></ul>
  19. 19. <ul><li>Both RNA and DNA viruses have been shown to be capable of causing cancers in various vertebrate species including man. </li></ul><ul><li>Integrate there genetic material into the DNA of the host cell. </li></ul>
  20. 20. <ul><li>EBV: Africans </li></ul><ul><li>Burkitt’s lymphomas </li></ul><ul><li>Nasopharyngeal carcinomas. </li></ul><ul><li>98% of the tumour cells show EBV genom </li></ul><ul><li>High antibody levels in the serum. </li></ul><ul><li>Human papilloma virus. </li></ul><ul><li>Type 5.6,11 papillomas </li></ul><ul><li>Type 16 & 18 involved in cervical carcinomas. </li></ul><ul><li>Hepatitis B: Hepatocellular carcinoma. </li></ul>
  21. 21. <ul><li>CHEMICAL CARCINOGENESIS </li></ul><ul><li>Epidemiological evidence shows that there is a large number of chemicals with carcinogenic properties </li></ul><ul><li>Eg Industrial cancers (Occupational cancers); </li></ul><ul><li>Result of prolong exposure to chemical carcinogens. </li></ul><ul><li>Scrotal cancers - Chimney sweepers (Percival Pott in 1775) </li></ul><ul><li>Skin cancers - Tar workers </li></ul><ul><li>Bladder cancers - Aniline die workers (1895) </li></ul><ul><li>Liver angiosarcomas - PVC factory workers </li></ul><ul><li>Lung cancers - Asbestos workers </li></ul>
  22. 22. Experimental evidence for chemical carcinogens <ul><li>1917 (Yamagiwa and Itchikawa) </li></ul><ul><li>Coal tar application in rabbit skins Polycyclic hydrocarbons ; Dibenzanthracene Methyl cholanthrene </li></ul><ul><li>Benzpyrene (carcinogens) </li></ul><ul><li>It has been shown that most of the Poly cyclic hydrocarbons, Aromatic amines Nitrosamines, aflatoxins are carcinogenic. </li></ul><ul><li>mineral oils/fuels, atmosphere of industrialized cities </li></ul>
  23. 23. Action of chemical carcinogens <ul><li>Direct acting carcinogens: </li></ul><ul><li>Need no activation </li></ul><ul><li>Electrophilic form </li></ul><ul><li>Weak carcinogens </li></ul><ul><li>Procarcinogens: Poly cyclic hydrocarbons, Aromatic amines Nitrosamines, </li></ul><ul><li>Aflatoxins </li></ul>
  24. 24. <ul><li>How do chemical carcinogens including poly cyclic hydocarbons act. </li></ul><ul><li>Procarcinogens Ultimate carcinogens </li></ul><ul><li>(Carcinogen compo) </li></ul><ul><li>( Ultimate carcinogens ) </li></ul><ul><li>Positively charged Negatively charged electrophilic reactants proteins & N acids ++++ - - - - (Elec dense) </li></ul><ul><li>Insertion of a reactant between bases of the DNA leads to alter the base pair (mutations). </li></ul>Hydroxylation
  25. 25. <ul><li>Benzidine and derivatives ; </li></ul><ul><li>Used in Laboratories (Occult blood) /Industries Induce bladder cancers </li></ul><ul><li>Dimethylaminoazobenzene (Butter yellow); Induced liver cancers (Hepatomas ) </li></ul><ul><li>Asbestos (silicates); </li></ul><ul><li>Malignant Mesotheliomas of the pleura Bronchial carcinomas </li></ul><ul><li>PVC (v c monomer); Haemangiosarcoma in the liver </li></ul><ul><li>Habits; Betel/smoking(Oral/Lung) </li></ul>
  26. 26. <ul><li>Preservatives; </li></ul><ul><li>Nitrites in meat Nitrites + HCl= Nitrous sausages acid </li></ul><ul><li>Nitrosamines s econdary + </li></ul><ul><li>(Carcinogenic) amines </li></ul><ul><li>Aflatoxine; </li></ul><ul><li>(Metabolites of Aspergillus flavus) </li></ul><ul><li>liver cancer </li></ul>
  27. 27. <ul><li>Bladder cancer in rubber industry workers </li></ul><ul><li>Liver </li></ul><ul><li> -naphtylamine 1 hydroxy 2 naphtylamine Conjugate with Glucuronic Acid </li></ul><ul><li>Doges/ humans </li></ul><ul><li>secretion of Glucuronidase </li></ul><ul><li>in the bladder Glucuronide </li></ul><ul><li>Excrete in urine </li></ul><ul><li>The example of remote carcinogenesis </li></ul>
  28. 28. <ul><li>Features of chemical carcinogens </li></ul><ul><li>Induction of cancer: </li></ul><ul><li>Dose dependent </li></ul><ul><li>Duration of exposure </li></ul><ul><li>Dosage- Light smoking -- cancers </li></ul><ul><li>Heavy smoking -- no </li></ul><ul><li>Individual susceptibility </li></ul><ul><li>Genetic predisposition </li></ul>
  29. 29. <ul><li>Chemical carcinogenesis involves two distinct but sequential effects on cells. </li></ul><ul><li>Initiation </li></ul><ul><li>Promotion </li></ul>
  30. 30. <ul><li>Initiation and promotion; </li></ul><ul><li>Skin of mice: (Compete Carcinogen) </li></ul><ul><li>Methylcholanthrene long time Cancer </li></ul><ul><li>Croton oil </li></ul><ul><li>(Promoter/co-carcinogens) </li></ul>
  31. 31. <ul><li>Initiation </li></ul><ul><li>Chemical carcinogens are initiating agents, </li></ul><ul><li>Two steps: </li></ul><ul><li>Alteration in DNA </li></ul><ul><li>Mitosis </li></ul><ul><li>Initiation is an irreversible process. </li></ul><ul><li>Initiated cells can be silent for long time. Carcinomas develop ones a promoter is available. </li></ul>
  32. 32. Promotion: <ul><li>The steps involved in this is not known. </li></ul><ul><li>Selective proliferation of initiated cells. </li></ul><ul><li>Nonspecific </li></ul><ul><li>Slow acting. </li></ul><ul><li>Reversible at least at the beginning . </li></ul>