carcinogenesis Flashcards
define carcinogen
carcinogen - a substance capable of causing cancer in living tissue
define initiator
initiator - substance which causes the initial mutation
define promoter
promoter (accelerator) - substances which enhance the tumourigenecity after the initiator has caused a mutation
define latent period
latent period - the gap between the initial exposure event to the carcinogen and the presentation of tumours
carcinogens with the tumours they induce
carcinogen | tumour induced |
| — | — |
| asbestos | bronchogenic carcinomas/mesothelioma (chest cavity) |
| UVB | melanoma |
| ionising radiation | skin cancer/leukaemia/bone cancer/thyroid cancer |
| aflatoxin | liver cancer |
| naphthylamine | bladder |
| benzpyrene | lung cancer |
major categories of carcinogens:
- chemicals e.g smoking
- radiation e.g UV, ionizing radiation
- some parasites, fungal toxins e.g aflaxatoxin
- viruses
chemical carcinogenesis:
- what is the carcinogen?
- what is the promoter?
what are the multi-steps process?
chemical carcinogenesis
1. carcinogen = methyl-cholanethrene
2. promoter = croton oil - TPA
- initiation
- promoter
- progression (irreversible)
describe the multi-step process of chemical carcinogenesis?
- initiation: Initiation (mutagenic) event involves cellular genome mutations in tumour suppressor genes and oncogenes
- promoter: Promotion (reversible, not mutagenic) Stimulates proliferation and causes both mutated and normal cells to proliferate. e.g. TPA (phorbol esters), dioxin (polycyclic aromatic compounds)
- progression (irreversible): irreversible enhancement/ repression of gene expression. Selection of neoplastic cells for optimal growth genotype/ phenotype in response to the cellular environment
order of carcinogenesis:
high dose of carcinogen = tumours develop (carcinogen acts as both initiator and promotor/accelerator)
low dose of carcinogen = no tumours develop
multiple doses of promoter = no tumours develop
low dose of carcinogen + promoter = tumours develop
when is the latent period longer?
latent period is longer when the onset of promoters is later after initial dose of carcinogen
chemical carcinogenesis of the bladder:
what causes chemical carcinogenesis of the bladder?
what is the mechanism of processing in the body?
what does the latent period of onset and risk of bladder cancer depend on?
2-napthylamine used in the dye industry
- it is toxic due to the way its processed in the body:
mechanism
1. aromatic amines such as 3-naphthylamine are pre-carcinogens requiring activation
2. it enters the liver, which converts 2NTA to carcinogenic metabolite-2-amino-naphthal
3. metabolite 2-naphthal is detoxified to glucuronide which is extreted by kidneys and enters the bladder
4. in the bladder, human urothelial cells express beta-glucuronidase
5. the bladder converts glucoronide to a carcinogen (o-aminophenol)
the latent period of onset and risk of bladder cancer depends on the length of carcinogen exposure
chemical carcinogenesis of the lung:
what causes bronchogenic carcinomas?
what causes mesothelioma?
what does risk depend on?
what is the mechanism of processing in the body?
Asbestosis (formation of scar tissue in the lung as a result of exposure) more commonly predisposes to bronchogenic carcinomas, increasing the risk by a factor of five
- However, exposure to ‘blue’ asbestos fibres carries a risk of Mesothelioma
- Mesothelioma is a rare tumour that has a 25 – 45 year latent period
- Risk depends on the duration and intensity of exposure
- Risk of asbestos-related cancer is higher (1:50) in smokers as compared with non-smokers exposed to asbestos
mechanism
1. abestos is fibrous silicate substance which can be inhaled
2. when inhaled, the needle-like fibres become coated in proteins forming asbestos bodies
3. the presence of asbestos bodies excites a macrophage and gaint cell response, rather like silicosis
chemical carcinogenesis of the lung: smoking and cancer
what causes cancer of smoking-induced lung cancer?
what are 2 genes most frequently mutated in smoking-related lung cancers?
what is the mechanism of processing in the body?
- benzoprene leads to guanine mutations in K-Ras and p53 in the regions found to be mutated in smoking-induced lung cancers
- K-ras and p53 are two genes most frequently mutated in smoking-related lung cancers
- cells treated with Benzopyrene show the same spectrum of mutations as found in the K-ras and p53 of smokers
mechanism
1. The active carcinogen in tobacco smoke is the polycyclic aromatic
hydrocarbon 3,4-benzpyrene (benz[a]pyrene)
2. This polycyclic aromatic hydrocarbon is converted by Aryl Hydrocarbon Hydroxylase (AHH*) into:
3. Benzo[a]pyrene diol epoxide that binds to DNA forming damaging products
*AHH is upregulated in smokers
detoxification of carcinogens:
- what chemical detoxifies carcinogens?
- what do some individuals have?
- what do homozygous null individuals have an increased risk of?
- why do some smokers don’t develop lung cancer?
- Glutathione S transferase (GSTM1) detoxifies carcinogens
- Some individuals have null genotype so no GSTM1 protein is detectable
- GSTM1 is polymorphic in the population, being null in about 30-50% of individuals depending on the ethnic group from which they come
- Homozygous null individuals have an increased risk of lung cancer
and smoking-induced bladder cancer - Not all heavy smokers develop lung cancer. In these smokers AHH may not be expressed – DNA-binding epoxides are therefore not generated
describe chemical carcinogenesis following chemotherapy
- Although rare, secondary carcinogenesis can occur from the use of
alkylating agents in chemotherapy - Risk of secondary tumours following cancer treatment
- These result from DNA-damage inflicted on surviving normal
somatic cells during treatment - DNA strand-breakage and base damage induced
