This document discusses the aetiology of neoplasia (tumor development). It identifies several risk factors for cancer development including age, genetics, environment, and lifestyle habits. It describes how various carcinogenic agents like chemicals, radiation, viruses, and hormones can cause DNA damage and genetic mutations over time, leading to cancer initiation and promotion. Specifically, it explains how ionizing radiation, ultraviolet light, viruses, chemicals, and hormones may contribute to cancer development and progression through their effects on DNA and cell proliferation.

1. Neoplasia Aetiology

2. Aetiology

3. Introduction 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.

4. Risk factors for a cancer Age Genetic factors. Geographical Racial factors Environmental factors.

5. The possible causative agents of carcinogenesis Chemical carcinogens Physical carcinogens Viruses Hereditary factors Hormones Cancers associated with chronic diseases

6. Physical agents Ionizing radiation: UV radiation

7. What happens when exposed Radiation causes its effect by transferring energy to the substance through which it passes Result may be: Ionization Change in the energy state of the electrons or charged molecules.

8. Physical agents Ionizing radiation: X rays ,  ,  and  rays These agents injure the cells through which it pass by dislodging ions from water and other molecules– Formation of free radicals. React with DNA nucleic acids, proteins,and other molecules. DNA damages may be; Point mutation (Changes in single bases) Breaks in the DNA double strand (wrong reunion)

9. Lethal doses - Immediate cell death Sub lethal doses - Permanent damage in DNA. Malignant transformation. Effect of the radiation on different tissues depends on the Nature of the tissues (Bone) Type of radiation (Determined the depth of penetration)

10. Evidence to show effects of ionized radiation Nuclear weapons testing; Radio strontium Hiroshima and Nagasaki (1945) - leukaemias & other cancers Dial painters (Osteosarcomas). Radiologists

11. UV light: Farmers with fair skin who have no melanin protection. (Solar keratosis) lip cancers, Squamous cell carcinomas Basel cell carcinomas Malignant melanomas Mechanism; Dimmer formation between bases E.g.:Thymidine bases in the DNA. (Dimer causes mutation in DNA replication) Xeroderma Pigmentosum: Lack of enzyme involved in the repair mechanism of damaged DNA.

12. Hormones Relationship between neoplasia and hormones is complex.

13. Animal experiments to show hormonal involvement in carcinogenesis: Mice: High cancer strains oestregen Breast cancers Low cancer strains oestregen Hyperplasia Mice or rats. Two ovaries were removed and one implanted in the spleen to stop the feed back inhibition of pituitary. (result is occasional ovarian tumours) Mice or rats Low I, diet and thiouracil Reduce thyroxin formation (no feed back effect) Result is thyroid hyperplasia/ademoma/carcinomas

14. However evidence of hormonal involvement in human tumours are rare. But association of hormones in tumours in man have been shown Granular cell OESTROGEN tumour of the ovary Endometrial Endometrial hyperplasia Carcinoma Artificial sex Oestrogen Enlargement of change Breast Carcinoma Hyperplasia

15. Hormone dependency ; 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 30% Breast tumours, are hormone dependent Later hormonal dependent Independent.

16. Hereditary predisposition ; Cancer of the breast Cancer families Hereditary diseases; Polyposis coli: Autosomal dominant Retinoblastoma Xeroderma pigmentation

17. Virus and cancer Ellerman and Band (1908) Chicken Cell free extract Erythroid leukaemia

18. Rous (1911) Chicken Cell free extract Sarcoma of sarcoma Bittner(1936): Foster mothers from cancer free strains New bone mice with cancer susceptible strains New bone mice from cancer free strains Foster mothers from cancer strains

19. Both RNA and DNA viruses have been shown to be capable of causing cancers in various vertebrate species including man. Integrate there genetic material into the DNA of the host cell.

20. EBV: Africans Burkitt’s lymphomas Nasopharyngeal carcinomas. 98% of the tumour cells show EBV genom High antibody levels in the serum. Human papilloma virus. Type 5.6,11 papillomas Type 16 & 18 involved in cervical carcinomas. Hepatitis B: Hepatocellular carcinoma.

21. CHEMICAL CARCINOGENESIS Epidemiological evidence shows that there is a large number of chemicals with carcinogenic properties Eg Industrial cancers (Occupational cancers); Result of prolong exposure to chemical carcinogens. Scrotal cancers - Chimney sweepers (Percival Pott in 1775) Skin cancers - Tar workers Bladder cancers - Aniline die workers (1895) Liver angiosarcomas - PVC factory workers Lung cancers - Asbestos workers

22. Experimental evidence for chemical carcinogens 1917 (Yamagiwa and Itchikawa) Coal tar application in rabbit skins Polycyclic hydrocarbons ; Dibenzanthracene Methyl cholanthrene Benzpyrene (carcinogens) It has been shown that most of the Poly cyclic hydrocarbons, Aromatic amines Nitrosamines, aflatoxins are carcinogenic. mineral oils/fuels, atmosphere of industrialized cities

23. Action of chemical carcinogens Direct acting carcinogens: Need no activation Electrophilic form Weak carcinogens Procarcinogens: Poly cyclic hydrocarbons, Aromatic amines Nitrosamines, Aflatoxins

24. How do chemical carcinogens including poly cyclic hydocarbons act. Procarcinogens Ultimate carcinogens (Carcinogen compo) ( Ultimate carcinogens ) Positively charged Negatively charged electrophilic reactants proteins & N acids ++++ - - - - (Elec dense) Insertion of a reactant between bases of the DNA leads to alter the base pair (mutations). Hydroxylation

25. Benzidine and derivatives ; Used in Laboratories (Occult blood) /Industries Induce bladder cancers Dimethylaminoazobenzene (Butter yellow); Induced liver cancers (Hepatomas ) Asbestos (silicates); Malignant Mesotheliomas of the pleura Bronchial carcinomas PVC (v c monomer); Haemangiosarcoma in the liver Habits; Betel/smoking(Oral/Lung)

26. Preservatives; Nitrites in meat Nitrites + HCl= Nitrous sausages acid Nitrosamines s econdary + (Carcinogenic) amines Aflatoxine; (Metabolites of Aspergillus flavus) liver cancer

27. Bladder cancer in rubber industry workers Liver  -naphtylamine 1 hydroxy 2 naphtylamine Conjugate with Glucuronic Acid Doges/ humans secretion of Glucuronidase in the bladder Glucuronide Excrete in urine The example of remote carcinogenesis

28. Features of chemical carcinogens Induction of cancer: Dose dependent Duration of exposure Dosage- Light smoking -- cancers Heavy smoking -- no Individual susceptibility Genetic predisposition

29. Chemical carcinogenesis involves two distinct but sequential effects on cells. Initiation Promotion

30. Initiation and promotion; Skin of mice: (Compete Carcinogen) Methylcholanthrene long time Cancer Croton oil (Promoter/co-carcinogens)

31. Initiation Chemical carcinogens are initiating agents, Two steps: Alteration in DNA Mitosis Initiation is an irreversible process. Initiated cells can be silent for long time. Carcinomas develop ones a promoter is available.

32. Promotion: The steps involved in this is not known. Selective proliferation of initiated cells. Nonspecific Slow acting. Reversible at least at the beginning .