Study Set Content:
Clonal expansion of the initiated cell population
Promotion
Modification is not enough to produce cancer Nonreversible
Initiation
Single treatment can induce mutation
Initiation
Increase in cell proliferation or decrease in cell death (apoptosis)
Promotion
Mutation, chromosome disarrangement
Progression
Changes from preneoplasia to neoplasia benign/malignan
Progression
Reversible
Promotion
Multiple treatments (prolonged treatment) necessary
Promotion
Irreversible Number of treatments needed with compound unknown (may require only single treatment
Progression
Threshold
Promotion
Directly interact with the nuclear DNA of a target cell • If this damage is unrepairable, DNA damage is inherited in subsequent daughter cells
GENOTOXIC/DNA-REACTIVE CARCINOGENS
Are highly reactive electrophilic molecules that can interact with and bind to nucleophiles, such as cellular macromolecules, including DNA without needing to be bio transformed into a reactive toxicant
DIRECT-ACTING (ACTIVATIONINDEPENDENT) CARCINOGEN
Usually produce their neoplastic effects at the target tissue where the metabolic activation of the chemical occurs and not at the site of exposure
INDIRECT-ACTING GENOTOXIC CARCINOGENS
Generally, these highly reactive chemicals frequently result in tumor formation at the site of chemical exposure.
DIRECT-ACTING (ACTIVATIONINDEPENDENT) CARCINOGEN
parent compound and requires metabolism to be carcinogenic
Procarcinogen
intermediate
Proximate carcinogen
– final metabolite
Ultimate carcinogen
• May result from misread DNA (through transitions or transversions), frame-shifting, or broken DNA strand.
Mutagenesis
The ultimate carcinogenic forms of these chemicals are frequently strong electrophiles.
DAMAGE BY ALKYLATING ELECTROPHILES
Following the formation of a carcinogen-DNA adduct, the persistence of the adduct is a major determinant of the outcome. This persistence depends on the ability of the cell to repair the altered DNA.
DNA Repair
