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.
Morales-Ramírez
Pedro
P
Departamento de Genética, Instituto Nacional de Investigaciones Nucleares, Apartado Postal 18-1027, México, DF Mexico. pmr@nuclear.inin.mx
Vallarino-Kelly
Teresita
T
Cruz-Vallejo
Virginia L
VL
López-Iturbe
Rosario
R
Alvaro-Delgadillo
Horacio
H
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004913:Erythrocytes, Abnormal; D005821:Genetic Techniques; D007700:Kinetics; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating