Paper I
Question
Chemical carcinogenesis
Answer
Chemical carcinogenesis occurs through direct or metabolically-activated chemical agents causing DNA damage, initiating a multistep process (initiation-promotion-progression).
Direct-acting carcinogens
- Require no metabolic conversion; relatively weak carcinogens
- Example: alkylating agents (e.g., cyclophosphamide — used therapeutically but carries risk of secondary malignancy)
Indirect-acting carcinogens (procarcinogens)
- Require metabolic activation (usually hepatic cytochrome P450 enzymes) to become active electrophilic carcinogens
- Polycyclic aromatic hydrocarbons (benzo[a]pyrene in tobacco smoke) — lung cancer
- Aromatic amines/azo dyes (beta-naphthylamine) — bladder cancer
- Aflatoxin B1 (Aspergillus flavus-contaminated food) — hepatocellular carcinoma (especially with concurrent HBV infection)
- Nitrosamines (smoked/processed foods) — gastric and oesophageal cancer
- Vinyl chloride — hepatic angiosarcoma
- Asbestos — mesothelioma, lung carcinoma
Mechanism (initiation and promotion)
- Initiation: Exposure of cells to a carcinogenic (mutagenic) agent, causing permanent DNA damage/mutation in a single cell — this is rapid and irreversible but insufficient alone to cause cancer
- Promotion: Repeated exposure to a promoting agent (not itself mutagenic) induces proliferation of the initiated (mutated) cell population, increasing the chance of additional mutations accumulating — this step is reversible if the promoting stimulus is removed early
- Progression: Accumulation of additional mutations in the expanding clone leads to increasingly aggressive, invasive, and metastatic behaviour
Key molecular targets
- Activated carcinogen metabolites form DNA adducts, causing mutations preferentially in proto-oncogenes (e.g., RAS) and tumour suppressor genes (e.g., TP53)