Initiation

• • Induction of a mutation in an essential gene involved in cell growth
  • activation of oncogenes
  • inactivation of tumor suppressor genes, DNA repair genes, genes in

  antioxidation response
• Requires a few rounds of cell division for the ‘fixation’ of the DNA damage

  • Fixation is not repair; Fixation = keep mutation in divided cells
• • DNA damage not enough to produce cancer
  • Non reversible
  • single treatment of genotoxic carcinogen --> induce mutation
• Outcomes of initiated cells:

  • remain in a static nondividing state
  • acquire mutations incompatible with viability/ normal function; This cell will be removed by apoptosis
  • undergo cell division --> selective growth and expansion of the

  initiated cell population, through intrinsic or extrinsic factors
• Initiators

  • chemical carcinogens that function at the initiation stage
  • Highly reactive electrophiles
  • Interact with nucleophiles in the cell (i.e., DNA, RNA, and protein)
  • Directly mutagenic
  • Once the injury to the DNA has occurred and is not repaired, the cell is permanently mutated
• Some initiated cell following high dose exposure and/ or repeated dosing to genetoxic agents may be capable of progressing through all 3 stages of carcinogeneis

  • these agents are called Complete Carcinogens