In vivo kinetics of micronuclei induction by bifunctional alkylating antineoplastics

The aim of the present study was to determine in vivo the kinetics of micronucleated polychromatic erythrocyte (MN‐PCE) induction in mice, as an approach for studying the mechanism of micronuclei induction by mitomycin C, cis‐diamine dichloroplatinum, busulfan and bis‐chloroethylnitrosourea, bifuctional alkylating antineoplastic agents having different patterns of crosslink induction. The kinetics of MN‐PCE induction was established by scoring the frequency of MN‐PCE in 2000 PCE in peripheral blood, for periods of 8 or 10 h after acute treatment and up to 80 h, with different doses of the agent. The kinetics of MN‐PCE induction and particularly the times of maximal induction by different bifunctional alkylating agents were compared with the kinetics previously obtained for ethylnitrosourea, methylnitrosourea and 6‐mercaptopurine, agents that cause MN‐PCE mainly in the first, second and third divisions after exposure, respectively. The results obtained in the present study allow us to conclude that: (i) bifunctional alkylating agents have very different efficiencies of genotoxic and cytotoxic action; (ii) all assayed bifunctional alkylating agents induced micronuclei during the first cell division, owing to the mistaken repair of primary lesions, e.g. excision; (iii) busulfan and bis‐chloroethylnitrosourea showed an additional late mechanism of micronuclei induction, which is expressed at the third division and seems to be related to the mismatch repair process.