Carcinogenesis

Question 1

what are the four main categories of carcinogens

Answer 1

• chemicals
• radiation
• some parasites and fungal toxins
• viruses

Question 2

chemical carcinogenesis the four stages

Answer 2

• initiation
• promotion (reversible)
• progression (irreversible)
• malignancy

Question 3

Initiation

Answer 3

this is a mutagenic event involves cellular genome mutations in tumour suppressor genes and oncogenes

Question 4

promotion

Answer 4

• this is NOT mutagenic
  stimulates proliferation and causes both mutated and normal cells to proliferate

TPA
dioxin

Question 5

Progression

Answer 5

irreversible enhancement/repression of gene expression

Selection of neoplastic cells for optimal growth genotype/phenotype in response to the cellular environment

Question 6

High dose of carcinogen

Answer 6

tumours develop (carcinogen acts as both
initiator and promotor/accelerator)

Question 7

Low dose of carcinogen

Answer 7

no tumour develops

Question 8

multiple doses of promotor

Answer 8

no tumour develop

Question 9

low dose carcinogen + promotor

Answer 9

tumours develop

Question 10

occupational exposure examples

Answer 10

chimney sweeps

dye industry and bladder cancer

Question 11

dye industry and bladder cancer

Answer 11

carcinogen = 2-napthylamine
this requires activation
- LIVER = Converts 2NTA to carcinogenic metabolite 2-amino-naphthol
- this is then detoxified to gluronide which is excreted by the kidneys
BLADDER = urothelial cells express beta-glucuronidase
- this converts glucuronide to a carcinogen

Question 12

asbestos exposure

Answer 12

increasing the risk by a factor of five
Risk depends on the duration and intensity of exposure
(1:50) in smokers
When inhaled, the needle-like fibres become coated in proteins (asbestos bodies) and their presence excites a macrophage and giant cell response, rather like silicosis

Question 13

Cigarette smoking and cancer

Answer 13

1 : 22 increased lung cancer risk
- K-Ras and p53 are the 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.
GUANINE MUTATIONS

Question 14

Carcinogen in tobacco smoke

Answer 14

hydrocarbon 3,4-benzpyrene which is then converted to Aryl Hydrocarbon Hydroxylase (AHH) and then into Benzoapyrene diol epoxide that binds to DNA forming damaging products

Question 15

what detoxifies carcinogens

Answer 15

Glutathione S transferase (GSTM1)

Question 16

Risk from carcinogens in diet

Answer 16

Gut bacteria convert nitrites and nitrates

Nitrosamines – carcinogens that can lead to cancers of gastro-intestinal tract and liver

Question 17

Aflatoxicosis

Answer 17

Aflatoxicosis is poisoning, especially of the liver
that results from ingestion of aflatoxins from contaminated food.
- Aflatoxin B1 is a potent carcinogen in both human and animal species

Question 18

Why is there such a large difference between cases of small and large intestine cancer

Answer 18

Bcl2 (which is expressed in the colonic epithelium but not small intestine) increased expression suppresses apoptosis increases cell survival

Question 19

UV radiation

Answer 19

• Non-ionising (causes excitation of atoms)
• Damage DNA
• Form pyrimidine dimers but can also break DNA by indirect mechanisms
• Caucasians susceptible to melanoma and basal cell carcinoma

Question 20

Radiation carcinogenesis

Answer 20

• Necroses and skin cancers were common amongst early radiologists before the risks were appreciated
• X-ray sources were used with total lack of protection