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Ahmed Group Lecture 26 Radiation-induced carcinogenesis Lecture 26.

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Presentation on theme: "Ahmed Group Lecture 26 Radiation-induced carcinogenesis Lecture 26."— Presentation transcript:

1 Ahmed Group Lecture 26 Radiation-induced carcinogenesis Lecture 26

2 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Mechanism of carcinogenesis 3-multi step hypothesis Oncogene/anti-oncogene hypothesis Four stage hypothesis

5 Ahmed Group Lecture 26 Radiation-Induced Carcinogenesis Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis.

6 Ahmed Group Lecture 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 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Concept of oncogene model

9 Ahmed Group Lecture 26 Chromosomal changes leading to oncogene activation in human malignancies

10 Ahmed Group Lecture 26 Loss of tumor suppressor gene

11 Ahmed Group Lecture 26 Rb : Familial vs Sporadic

12 Ahmed Group Lecture 26 Most common tumor suppressor genes

13 Ahmed Group Lecture 26 Process of Somatic homozygosity

14 Ahmed Group Lecture 26 Cooperating genes

15 Ahmed Group Lecture 26 Four-stage hypothesis Chromosomal damage in normal dividing cells Defect in differentiation genes Gene defect in hyperplastic cells Gene defect in cancer cells

16 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Colon tumor model

20 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Dose-response relationship of radiation-induced cancer

22 Ahmed Group Lecture 26 Radiation as a carcinogen Evidence comes from: Tissue culture model Animal model Human model

23 Ahmed Group Lecture 26 Tissue culture model

24 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Transformation per irradiated cell

26 Ahmed Group Lecture 26 Enhancers

27 Ahmed Group Lecture 26 Protectors

28 Ahmed Group Lecture 26 Transformation incidence of irradiated cells

29 Ahmed Group Lecture 26 Radiation + promoter IR C3H 10T1/2 cells IR+TPA

30 Ahmed Group Lecture 26 Supression of radiation- induced transformation

31 Ahmed Group Lecture 26 Animal Model

32 Ahmed Group Lecture 26 Radiation-induced leukemia

33 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Alterations in oncogenes in radiation-induced cancer

35 Ahmed Group Lecture 26 Human Model

36 Ahmed Group Lecture 26 Marie Curie and Irene

37 Ahmed Group Lecture 26 Hand of dentist

38 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Leukemia Survivors of the A-bomb attacks on Hiroshima and Nagasaki Patients treated with ankylosing spondylitis

41 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Thyroid cancer incidence

43 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Basal cell carcinoma

45 Ahmed Group Lecture 26 Basal cell carcinoma

46 Ahmed Group Lecture 26 Risk of cancer following iodine-131 therapy

47 Ahmed Group Lecture 26 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 Ahmed Group Lecture 26 Quantitative risk estimates for radiation-induced cancer

49 Ahmed Group Lecture 26 Quantitative risk estimates for radiation- induced cancer

50 Ahmed Group Lecture 26 Breast cancer incidence

51 Ahmed Group Lecture 26 Breast Cancer Japanese female survivors of the A- bomb attacks on Hiroshima and Nagasaki Female patients in a Nova Scotia sanatorium subjected to multiple flouroscopies during artificial pneumothorax for pulmonary tuberculosis Females treated for postpartum mastitis and other benign conditions

52 Ahmed Group Lecture 26 Bone Cancer Young persons, mostly women, employed as dial painters, who ingested radium as a result of licking their brushes into a sharp point while applying luminous paint to watches and clocks Patients given injections of radium-224 for the treatment of tuberculosis or ankylosing spondylitis

53 Ahmed Group Lecture 26 Lung cancer Persons exposed to external sources of radiation, including the Japanese survivors and those with the ankylosing spondylysis Underground miners exposed to radon in the mine atmosphere

54 Ahmed Group Lecture 26 Bone sarcoma incidence

55 Ahmed Group Lecture 26 Skin cancer Radiologist Dentist X-ray technician Squamous cell and basal cell carcinoma have been most frequently observed

56 Ahmed Group Lecture 26 Oncogenes in human radiation-induced tumors Ras point mutations were also reported in human radiogenic tumors Other oncogenes which are of prime importance in the transformation / progression of radiogenic tumors is RET oncogene in radiation-induced thyroid tumors and c-myc gene amplification in other types of radiogenic tumors

57 Ahmed Group Lecture 26 In humans, it has been reported that mutations in the p53 gene is a potential marker of radon-associated lung cancers from uranium miners Higher incidence of p53 mutations were reported in thyroid carcinomas in children exposed to Chernobyl accident when compared to studies on patients who had no history of radiation exposure On the contrary, a lower incidence of mutation (2/33) and overexpression (4/33) of p53 was reported in PTC from children exposed to radiation after Chernobyl accident p53 in human radiation- induced tumors

58 Ahmed Group Lecture 26 Calculations based on risk estimates

59 Ahmed Group Lecture 26 Dose and Dose-Rate Effectiveness Factor (DDREF)

60 Ahmed Group Lecture 26 Quantitative risk estimates for a number of specific cancer sites

61 Ahmed Group Lecture 26 Summary of risk estimates For the population composed of both sexes the ICRP recommends the following figures

62 Ahmed Group Lecture 26 Summary More than one theory on the mechanism of carcinogenesis Evidence indicate that genes such as oncogenes and anti-oncogenes are implicated in radiogenic tumors. Experiments from tissue culture model and also observations from humans exposed to radiation (unintentionally and accidently) strongly suggests that radiation is a potent carcinogen. Radiation can induced malignancy such as leukemia, breast cancer, lung cancer, bone cancer etc., depending on the latent period.


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