Genotoxic Carcinogen
Genotoxic Carcinogen act directly on DNA to cause cancer, such as chemical carcinogens, eg, Benzo[a]pyrane of cigarette smoke, physical carcinogens, eg, UV radiation, and biological carcinogens, eg, EBV/HPV.
Cancer development is a multi-step process involving initiation, promotion, and progression. The initiator or in vivo metabolites, eg, Benzo[a]pyrane, cause irreversible mutation to DNA that becomes susceptible to promoter action for being transformed into cancer cells. Initiators initiate carcinogenesis, and promoters, eg, DDT, β-naphthoflavon, polybrominated biphenyls, etc, promote the proliferation of mutant cells, but promoters normally are ineffective if cells are not exposed to initiators. Progression, for instance, by benzoyl peroxide, other peroxides, oxidative stress, and inflammation, is an irreversible stepwise transformation to malignancy. Progression is associated with karyotypic changes related to increased cell growth, invasiveness, metastasis, cell biochemistry and morphology alteration, etc. As virtually all cancer cells are aneuploid, ie, with a wrong number of chromosomes.
Genotoxic carcinogens are potentially mutagenic chemicals when inhaled, ingested, or penetrating the skin, capable of causing direct irreversible mutation in DNA, even at low doses. Chemicals that do not act directly on DNA but interfere with normal cell proliferation through interaction with proteins involved in cell proliferation are non-genotoxic carcinogens. Some genotoxic chemical carcinogens are direct-acting, eg, alkylating and acylating agents like β-propiolactone, Dimethyl sulfate, and indirect-acting agents/pro-carcinogens eg, Polycyclic aromatic hydrocarbons, eg, Benz(a)anthracene, Benz(a)pyrene, in cigarette smoke; azo dyes.
A human can be exposed endogenously (maybe through the metabolism of some non-carcinogenic entities) or exogenously to genotoxic agents, eg, formaldehyde, alkylating agents, β₁, benzo[a]pyran, etc. Some metal compounds, eg, specific oxide of arsenic, act indirectly as a genotoxic agent through their interaction with cellular response to DNA damage.
Chemical carcinogens can cause cancer via (i) Point mutations- the replacement of a single nucleotide base with another nucleotide (ii) Frame-shift mutations- addition or deletion of a nucleotide such that in both cases, the protein sequence from that point onward is altered (iii) Chromosomal aberrations- any change in the normal structure or number of chromosomes (iv) Aneuploidy- chromosome number (23) is not a multiple of the normal haploid (v) Polyploidy- more than twice the haploid number of chromosomes. [Mamun Rashid Chowdhury]
