Initiation and promotion

When cells are initially exposed to a carcinogenic agent, genetic carcinogens interact with DNA to form an adduct or to induce chemical alterations of DNA. DNA adducts may result in damage by inducing point mutations, deletions, or chromosomal translocations. When changes are induced in genes involved in cell growth regulation or differentiation (e.g. oncogenes and tumour suppressor genes), cell transformation can result.

The majority of chemical carcinogens are metabolically activated, leading to the formation of reactive species—the ultimate carcinogen. Metabolism is frequently mediated by cytochrome P450 but in tissues and organs with low levels of cytochrome P450, the peroxidase component of prostaglandin synthetase or lipozygenase can activate. Metabolism involves enzymes mainly in the body's entry routes— respiratory tract, gastrointestinal tract, and liver—though metabolism may occur elsewhere, leading to organ-specific tumours.

Cytochrome P450 exists as a number of isoforms, each having a different substrate selectivity. Activity and substrate specificity of both activating and detoxifying enzymes varies from organ to organ, individual to individual, and species to species, resulting in organ- and species-specific carcinogencity. If the affected cell neither dies nor reverts to a normal cell through error-free DNA repair, initiation becomes irreversible after the cell undergoes replication.

The initiated tumour cell, with altered genotype and phenotype, may remain dormant for a long time before becoming a tumour, in the presence of a promoter, which may be one of a wide variety of chemicals. Promotion is reversible, so for an initiated cell to continue to replicate, it must be exposed to a promoter more or less continuously. Carbon tetrachloride is a well-known example of a promoter resulting in liver cancer in animal studies. Hormones can also act as promoters e.g. thyroid hormone is a promoter of thyroid cancer. Like initiation, progression is an irreversible process.

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