Lecture 26 Radiationinduced carcinogenesis Lecture 26 Ahmed Group
- Slides: 62
Lecture 26 Radiation-induced carcinogenesis Lecture 26 Ahmed Group
• 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 Lecture 26 Ahmed Group
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). Lecture 26 Ahmed Group
Mechanism of carcinogenesis • 3 -multi step hypothesis • Oncogene/anti-oncogene hypothesis • Four stage hypothesis Lecture 26 Ahmed Group
Radiation-Induced Carcinogenesis • Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis. Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
Concept of oncogene model Lecture 26 Ahmed Group
Chromosomal changes leading to oncogene activation in human malignancies Lecture 26 Ahmed Group
Loss of tumor suppressor gene Lecture 26 Ahmed Group
Rb : Familial vs Sporadic Lecture 26 Ahmed Group
Most common tumor suppressor genes Lecture 26 Ahmed Group
Process of Somatic homozygosity Lecture 26 Ahmed Group
Cooperating genes Lecture 26 Ahmed Group
Four-stage hypothesis • Chromosomal damage in normal dividing cells • Defect in differentiation genes • Gene defect in hyperplastic cells • Gene defect in cancer cells Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
Colon tumor model Lecture 26 Ahmed Group
• 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 Lecture 26 Ahmed Group
Dose-response relationship of radiation-induced cancer Lecture 26 Ahmed Group
Radiation as a carcinogen Evidence comes from: • Tissue culture model • Animal model • Human model Lecture 26 Ahmed Group
Tissue culture model Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
Transformation per irradiated cell Lecture 26 Ahmed Group
Enhancers Lecture 26 Ahmed Group
Protectors Lecture 26 Ahmed Group
Transformation incidence of irradiated cells Lecture 26 Ahmed Group
Radiation + promoter IR+TPA IR C 3 H 10 T 1/2 cells Lecture 26 Ahmed Group
Supression of radiationinduced transformation Lecture 26 Ahmed Group
Animal Model Lecture 26 Ahmed Group
Radiation-induced leukemia Lecture 26 Ahmed Group
Radiation-induced tumors in mice • • • Lecture 26 Lung cancer Bone tumor Breast tumor Ovarian tumor Uterine carcinomas • Skin cancer • Alimentary tract tumors • Thyroid cancer • Pituitary tumors • Adrenal tumors Ahmed Group
Alterations in oncogenes in radiation-induced cancer Lecture 26 Ahmed Group
Human Model Lecture 26 Ahmed Group
Marie Curie and Irene Lecture 26 Ahmed Group
Hand of dentist Lecture 26 Ahmed Group
• 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 Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
Leukemia • Survivors of the A-bomb attacks on Hiroshima and Nagasaki • Patients treated with ankylosing spondylitis Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
Thyroid cancer incidence Lecture 26 Ahmed Group
• 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 Lecture 26 Ahmed Group
Basal cell carcinoma Lecture 26 Ahmed Group
Basal cell carcinoma Lecture 26 Ahmed Group
Risk of cancer following iodine-131 therapy Lecture 26 Ahmed Group
• 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 Lecture 26 Ahmed Group
Quantitative risk estimates for radiation-induced cancer Lecture 26 Ahmed Group
Quantitative risk estimates for radiationinduced cancer Lecture 26 Ahmed Group
Breast cancer incidence Lecture 26 Ahmed Group
Breast Cancer • Japanese female survivors of the Abomb 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 Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
Bone sarcoma incidence Lecture 26 Ahmed Group
Skin cancer Squamous cell and basal cell carcinoma have been most frequently observed • Radiologist • Dentist • X-ray technician Lecture 26 Ahmed Group
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 Lecture 26 Ahmed Group
p 53 in human radiationinduced tumors • In humans, it has been reported that mutations in the p 53 gene is a potential marker of radon-associated lung cancers from uranium miners • Higher incidence of p 53 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 p 53 was reported in PTC from children exposed to radiation after Chernobyl accident Lecture 26 Ahmed Group
Calculations based on risk estimates Lecture 26 Ahmed Group
Dose and Dose-Rate Effectiveness Factor (DDREF) Lecture 26 Ahmed Group
Quantitative risk estimates for a number of specific cancer sites Lecture 26 Ahmed Group
Summary of risk estimates For the population composed of both sexes the ICRP recommends the following figures Lecture 26 Ahmed Group
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. Lecture 26 Ahmed Group
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