Chemical Carcinogenesis - Mechanism

Definition

Mechanism: Initiation - Promotion - Progression

Chemical carcinogen
        ↓
Metabolic activation, if required
        ↓
Reactive electrophilic ultimate carcinogen
        ↓
Covalent binding to DNA → DNA adducts
        ↓
Failure of DNA repair + cell replication
        ↓
Permanent mutation = INITIATED CELL
        ↓
Repeated promoter exposure
        ↓
Clonal proliferation of initiated cells
        ↓
Additional mutations and selection of aggressive subclones
        ↓
Malignant tumour

1. Initiation

• Initiators are chemicals that cause irreversible DNA damage (mutation).
• The initiating chemical, or its active metabolite, is usually a highly reactive electrophile.
• Electrophiles react with electron-rich, nucleophilic sites in DNA and form DNA adducts.
• If the damaged DNA is not repaired before replication, the mutation becomes fixed and is transmitted to daughter cells.
• Thus, initiation is:
  • Rapid
  • Irreversible
  • Permanent
  • Dose-dependent
• An initiated cell is not necessarily a tumour cell, but it has acquired a heritable mutation and is susceptible to promotion.

2. Promotion

• Tumour promoters do not directly damage DNA and are generally non-mutagenic.
• They act only after initiation and stimulate proliferation of initiated cells.
• Repeated or sustained exposure to the promoter is required.
• Promotion produces clonal expansion of initiated cells.
• Increased cell proliferation allows accumulation of further mutations, ultimately producing malignant transformation.

1. Non-mutagenic and non-carcinogenic when used alone
2. Must follow exposure to an initiator
3. Require repeated/prolonged application
4. Their effect is reversible in the early phase
5. Promote cell proliferation and may alter differentiation, apoptosis, and tissue microenvironment

• Phorbol esters
• Hormones, especially unopposed estrogen
• Phenols
• Certain drugs
• Chronic inflammation, tissue injury, repair, and fibrosis

3. Progression

• With continuing proliferation, initiated cells acquire additional mutations.
• There is clonal selection of cells with survival and growth advantage.
• The tumour progressively develops malignant properties:
  • Autonomous growth
  • Resistance to apoptosis
  • Invasion
  • Metastasis
  • Genetic heterogeneity

Types of Chemical Carcinogens

A. Direct-acting carcinogens

• Do not require metabolic activation.
• They are already active and can directly cause DNA damage.
• Most are alkylating or acylating agents.

• β-Propiolactone
• Dimethyl sulfate
• Diepoxybutane
• Anticancer alkylating drugs such as cyclophosphamide, chlorambucil, and nitrosoureas

B. Indirect-acting carcinogens (procarcinogens)

• Require metabolic conversion to an active ultimate carcinogen.
• Usually activated by hepatic cytochrome P450-dependent monooxygenases.
• The active metabolite is an electrophile that forms DNA adducts.

Procarcinogen
      ↓  Cytochrome P450 activation
Ultimate carcinogen (electrophilic metabolite)
      ↓
DNA adduct formation
      ↓
Mutation in RAS, TP53, etc.
      ↓
Cancer

1. Polycyclic aromatic hydrocarbons
   • Benzo[a]pyrene in tobacco smoke
   • Produced during combustion of fossil fuels and in smoked or charbroiled food
   • Associated with lung cancer
2. Aromatic amines and azo dyes
   • β-Naphthylamine
   • Benzidine
   • Associated with urinary bladder carcinoma in dye and rubber workers
3. Aflatoxin B1
   • Produced by Aspergillus in poorly stored grains and nuts
   • Associated with hepatocellular carcinoma
4. Nitrosamines
   • Derived from nitrites used as food preservatives
   • Carcinogenic in several organs
5. Other occupational/environmental carcinogens
   • Vinyl chloride
   • Nickel
   • Chromium
   • Pesticides
   • Polychlorinated biphenyls

Conclusion

“All direct carcinogens and ultimate carcinogens are highly reactive electrophiles that form covalent DNA adducts. Mutation becomes permanent after DNA replication, while tumour promoters cause clonal expansion of initiated cells.”