Paper I
Question
Discuss chemical carcinogenesis with examples
Answer
Chemical carcinogenesis occurs through direct or metabolically-activated chemical agents causing DNA damage/mutation, initiating a multistep process of carcinogenesis (initiation, promotion, progression).
Direct-acting carcinogens
- Act without metabolic conversion; relatively weak carcinogens
- Examples: alkylating agents (e.g., cyclophosphamide — used therapeutically but carries a risk of secondary malignancy)
Indirect-acting (procarcinogens)
- Require metabolic activation (usually by cytochrome P450 enzymes in the liver) to become active carcinogenic (electrophilic) metabolites
- Polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene in tobacco smoke) — implicated in lung cancer
- Aromatic amines/azo dyes (e.g., beta-naphthylamine) — implicated in bladder cancer (aniline dye industry workers)
- Aflatoxin B1 (from Aspergillus flavus contaminating stored grains/nuts) — implicated in hepatocellular carcinoma, especially with concurrent hepatitis B infection
- Nitrosamines (found in smoked/processed foods) — implicated in gastric and oesophageal cancer
- Vinyl chloride — implicated in hepatic angiosarcoma
- Asbestos — implicated in mesothelioma and lung carcinoma
Mechanism
- Activated carcinogens are electrophilic and react with nucleophilic sites in DNA (guanine bases), forming DNA adducts and causing mutations in proto-oncogenes and tumour suppressor genes, initiating the carcinogenic process