Carcinogens Flashcards
What are the 4 major categories of carcinogens?
- Chemicals
- Radiation
- Some parasites, fungal toxins e.g. aflatoxin
- Viruses
What is the mechanism of chemical carcinogens?
Normal tissue –> (INITIATION) Altered genotype of an ‘initiated cell’–> (PROMOTION) New phenotype emerges resulting in clonal expansion of initiated cell –>(PROGRESSION) Malignant metastases
(MALIGNANCY)
What is meant by initiation?
(Mutagenic) event involves cellular genome mutations in tumour supressor genes and oncogenes
What is meant by promotion?
Promotion is reversible and not mutagenic and stimulates proliferation and causes both mutated and normal cells to proliferate.
What is meant by progression?
An irreversible enhancement/repression of gene expression.
Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment
What will happen if somebody is exposed to a high does of carcinogen?
Tumours will develop (the carcinogen will act as both an initiator and promotor)
What will happen if someone is exposed to a low dose of carcinogen?
No tumours develop
What will happen if someone is exposed to multiple doses of promoter
No tumours develop
Low dose carcinogen and promotor
Tumours will develop
What is 2-napthylamine and what is it linked to?
- Compound used in dyes
* Carcinogenic compound linked to bladder cancer
How does 2-Napthylamine act as a carcinogen?
- Exists as an aromatic amine which is a pre-carcinogen requiring activation
- The liver converts 2NTA to carcinogenic metabolite 2-amino-naphthol
- 2 amino-naphthol is detoxified to glucuronide (not a carcinogen) which is then excreted by the kidneys
- In the bladder, human urothelial cells express B-glucuronidase which converts the glucuronide to a carcinogen
What is asbestosis?
Formation of scar tissue in the lung as a result of exposure , predisposes to bronchogenic carcinomas
What does exposure of blue asbestos carry a risk for?
Mesothelioma
What is asbestos?
A fibrous silicate substance
What happens to asbestos when it is inhaled?
The needle-like fibres become coated in proteins (asbestos bodies) and their presence excites a macrophage and giant cell response
What is mesothelioma?
- Rare tumour
- Metastic spread is uncommon
- Bulky tumour that can fill the chest cavity
What is the active carcinogen in tobacco smoke?
Benzopyrene (polycyclic aromatic hydrocarbon 3,4-benzpyrene)
Describe the effect of Benzopyrene
Leads to Guanine mutations in K-Ras and p53 in the regions found to be mutated in smoking induced lung cancer s
What are the genes most frequently found to be mutated in smoking related lung cancers?
K-Ras and p53
How does benzopyrene cause damage?
• Converted byAryl Hydrocarbon Hydroxylase (AHH) in to benzo[a]apyrene diol epoxide which binds to DNA forming damaging adducts
What is unregulated in smokers putting them at a greater risk of lung cancer?
AHH (Aryl Hydrocarbon Hydroxylase) (in heavy smokers that do not develop lung cancer, AHH may not be expressed)
Aside from lung cancer, which cancers are there increased risk of developing in smokers?
- Oesophageal cancer
- Bladder
- Kidney
- Pancreas
What can secondary carcinogenesis occur from?
Alkylating agents in chemotherapy
What can secondary tumours develop from following cancer treatment?
- DNA damage inflicted on surviving normal somatic cells during treatment
- DNA strand-breakage and base damage induced
What risks do nitrites and nitrates carry?
- Pathway for the conversion of dietary nitrites and nitrates to carcinogens
- food additives and fertilisers that enter drinking water means it enters into the diet
- Gut bacteria convert nitrites and nitrates into nitrosamines- carcinogens that can lead to cancers of the GI tract and liver
What is Aflatoxicosis?
Poisoning, especially of the liver that results from the ingestion of aflatoxins from contaminated food
What is Aflatoxin B1
A potent carcinogen in both human and animal species which can predispose to liver cancer - p53 mutation
What is there such a large difference between the incidence of tumours in the large intestine and the small intestine?
- Bcl2 is expressed in colonic epithelium and protects damaged cells from dying
- Therefore cells survive and accumulate mutations, leading to carcinogenesis
- Bcl2 is not expressed in the crypts of the small intestine
What is UV radiation?
- Non-ionising
* Damages DNA and forms pyrimidine dimers but can also break DNA by indirect mechanisms
