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Radiation-induced carcinogenesis. 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

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Radiation-induced carcinogenesis


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slide2

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
effect of ionizing radiation
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).
mechanism of carcinogenesis
Mechanism of carcinogenesis
  • 3-multi step hypothesis
  • Oncogene/anti-oncogene hypothesis
  • Four stage hypothesis
radiation induced carcinogenesis5
Radiation-Induced Carcinogenesis
  • Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis.
3 steps
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

other hypothesis oncogene anti oncogene based
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
four stage hypothesis
Four-stage hypothesis
  • Chromosomal damage in normal dividing cells
  • Defect in differentiation genes
  • Gene defect in hyperplastic cells
  • Gene defect in cancer cells
chromosomal damage in normal cells
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.
defect in differentiation genes
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.
gene defect in hyperplastic cells
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.
slide20

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
radiation as a carcinogen
Radiation as a carcinogen

Evidence comes from:

  • Tissue culture model
  • Animal model
  • Human model
tissue culture model24
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.
radiation promoter
Radiation + promoter

IR+TPA

IR

C3H 10T1/2

cells

radiation induced tumors in mice
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
slide38

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
slide39

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.

leukemia
Leukemia
  • Survivors of the A-bomb attacks on Hiroshima and Nagasaki
  • Patients treated with ankylosing spondylitis
thyroid cancer
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
slide43

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
slide47

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
slide48

Quantitative risk estimates for

radiation-induced cancer

slide49

Quantitative

risk estimates

for radiation-

induced

cancer

breast cancer
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
bone cancer
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
lung cancer
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
skin cancer
Skin cancer

Squamous cell and basal cell carcinoma have been most frequently observed

  • Radiologist
  • Dentist
  • X-ray technician
oncogenes in human radiation induced tumors
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
p53 in human radiation induced tumors
p53 in human radiation-induced tumors
  • 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
slide58

Calculations based on

risk estimates

slide59

Dose and

Dose-Rate

Effectiveness

Factor

(DDREF)

slide60

Quantitative risk estimates for a

number of specific cancer sites

slide61

Summary of risk estimates

For the population

composed of both

sexes the ICRP

recommends

the following

figures

summary
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.