The search for the molecular lesions responsible for the induction of chromosomal damage by alkylating agents.

: Many studies associated specific DNA alkylation products with specific biological effects of alkylating agents. Studies dealing with the identification of DNA lesions that are responsible for chromosomal damage are reviewed in this paper. Although early evidence suggested that alkylation of high nucleophilicity centers such as N-7 of guanine was associated with genetic effects of alkylating agents, recent studies shifted the attention to the alkylation of oxygen atoms. The results of studies based on the use of cells with different capacities to repair O6-alkylguanine (O6-AlkGua) indicate a key role for this alkylation product in the induction of sister chromatid exchanges, chromosomal aberrations and micronuclei. Our own results on the influence of exogenous thymidine on the frequency of micronuclei induced by methylating and ethylating agents further suggest that mispairing of O6-AlkGua with thymine may be involved. Molecular dosimetry studies did not reveal any correlation between individual DNA alkylation products and the induction of chromosomal damage, indicating that multiple lesions are probably involved.