Radiation-induced carcinogenesis

1. Radiation-induced carcinogenesis Lecture 26

2. Initiation, promotion, progression • Dose response for radiation-induced cancers • Importance of age at exposure and time since exposure • Malignancies in pre-natally exposed children • Second tumors in radiation therapy patients • Effects of chemotherapy on incidence • Risk estimates in humans • Calculations based on risk estimates

3. Effect of Ionizing radiation • Electromagnetic radiation (such as X- and gamma rays) are indirect ionizing radiation which deposits energy in the tissues through secondary electrons. These electrons can damage the DNA directly or can interact with water, leading to the formation of hydroxyl radicals that can interact with DNA and the enzymes. These processes will disrupt biochemical pathways and produce changes that will lead to cell death, neoplasia (in the somatic tissue), or heritable genetic damage (in the reproductive tissue).

4. Mechanism of carcinogenesis • 3-multi step hypothesis • Oncogene/anti-oncogene hypothesis • Four stage hypothesis

5. Radiation-Induced Carcinogenesis • Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis.

6. 3- Steps • Initiation Initiating events in chromosomes (such as aberrations) or in DNA. Initiators are radiation, chemical carcinogens, UV etc • Promotion Low doses of tumor initiators are necessary to convert the initiated cells to cancer cells. Examples are TPA, phorbol esters, estrogen and excessive fat. • Progression Increased genetic instability resulting in aggressive growth phenotype

7. Other hypothesis (Oncogene/anti-oncogene based) • Activation of proto-oncogenes • Loss of anti-oncogenes • Infection with certain viruses • Substitution of normal promoters of proto-oncogenes with strong promoters of viruses • Chromosomal aberrations

8. Concept of oncogene model

9. Chromosomal changes leading to oncogene activation in human malignancies

10. Loss of tumor suppressor gene

11. Rb : Familial vs Sporadic

12. Most common tumor suppressor genes

13. Process of Somatic homozygosity

14. Cooperating genes

15. Four-stage hypothesis • Chromosomal damage in normal dividing cells • Defect in differentiation genes • Gene defect in hyperplastic cells • Gene defect in cancer cells

16. Chromosomal damage in normal cells • Low or high dose radiation exposure can lead to chromosomal damage in normal cells. These cells may die, divide or differentiate.

17. Defect in differentiation genes • One or two normal damaged cells develop a defect in differentiation genes, which prevent them from a normal pattern of differentiation and death. Continuing division of these cells leads to hyperplasia and develop in adenoma.

18. Gene defect in hyperplastic cells • One or two hyperplastic cells in any adenoma can accumulate additional gene defects due to mutations or chromosomal damage, which can make them cancerous.

19. Colon tumor model

20. Initiation, promotion, progression • Dose response for radiation-induced cancers • Importance of age at exposure and time since exposure • Malignancies in pre-natally exposed children • Second tumors in radiation therapy patients • Effects of chemotherapy on incidence • Risk estimates in humans • Calculations based on risk estimates

21. Dose-response relationship of radiation-induced cancer

22. Radiation as a carcinogen Evidence comes from: • Tissue culture model • Animal model • Human model

23. Tissue culture model

24. Tissue culture model • Above 100 rads: the transformation frequency may exhibit a quadratic dependence on doses. • Between 30 and 100 rads: the transformation frequency may not vary with dose • Below 30 rads: the transformation frequency may be directly proportional to dose.

25. Transformation per irradiated cell

26. Enhancers

27. Protectors

28. Transformation incidence of irradiated cells

29. Radiation + promoter IR+TPA IR C3H 10T1/2 cells

30. Supression of radiation-induced transformation

31. Animal Model

32. Radiation-induced leukemia

33. Radiation-induced tumors in mice • Lung cancer • Bone tumor • Breast tumor • Ovarian tumor • Uterine carcinomas • Skin cancer • Alimentary tract tumors • Thyroid cancer • Pituitary tumors • Adrenal tumors

34. Alterations in oncogenes in radiation-induced cancer

35. Human Model

36. Marie Curie and Irene

37. Hand of dentist

38. Initiation, promotion, progression • Dose response for radiation-induced cancers • Importance of age at exposure and time since exposure • Malignancies in pre-natally exposed children • Second tumors in radiation therapy patients • Effects of chemotherapy on incidence • Risk estimates in humans • Calculations based on risk estimates

39. Importance of age at exposure and time since exposure Children and young adults are much more susceptible to radiation-induced cancer than the middle- and old-aged.

40. Leukemia • Survivors of the A-bomb attacks on Hiroshima and Nagasaki • Patients treated with ankylosing spondylitis

41. Thyroid Cancer • Survivors of the A-bomb attacks on Hiroshima and Nagasaki • Residents of the Marshall islands exposed to iodine-131 • Children treated with x-rays for an enlarged thymus • Children treated for diseases of the tonsils and nasopharynx • Children epilated with x-rays for the treatment of tinea capitis

42. Thyroid cancer incidence

43. Initiation, promotion, progression • Dose response for radiation-induced cancers • Importance of age at exposure and time since exposure • Malignancies in pre-natally exposed children • Second tumors in radiation therapy patients • Effects of chemotherapy on incidence • Risk estimates in humans • Calculations based on risk estimates

44. Basal cell carcinoma

45. Basal cell carcinoma

46. Risk of cancer following iodine-131 therapy

47. Initiation, promotion, progression • Dose response for radiation-induced cancers • Importance of age at exposure and time since exposure • Malignancies in pre-natally exposed children • Second tumors in radiation therapy patients • Effects of chemotherapy on incidence • Risk estimates in humans • Calculations based on risk estimates

48. Quantitative risk estimates for radiation-induced cancer

49. Quantitative risk estimates for radiation- induced cancer

50. Breast cancer incidence