Kinetic of genotoxic expression in the pharmacodynamics of busulfan.
BACKGROUND
Busulfan (BUS) is a highly toxic antineoplastic bifunctional-alkylating agent and has a narrow therapeutic window. Our previous study revealed a narrow dose-range of BUS, which causes a sudden dose-dependent transition from early- to late-expressing micronucleus induction and from a non-cytotoxic to a cytotoxic effect. In the present study, the kinetics of DNA-damaged cell induction by BUS and its dose-effect relationship were established.


METHODS
This was achieved by using the kinetics of DNA-damaged cell induction, determined by the comet assay in murine peripheral blood leukocytes of mice, after the intraperitoneal exposure to 16, 30, 45, 60 or 80 micromol/kg of BUS.


RESULTS
Doses of 15 or 30 micromol/kg of BUS were able to increase DNA-damaged cell frequency, but doses of 45 micromol/kg body weight or higher caused a sudden drop in this frequency.


CONCLUSIONS
This suggests that higher doses cause lesions that inhibit the expression of damage as comets, i.e., DNA-protein or interstrand crosslinks. The latter could be explained by sudden monoadduct-to-crosslink transformation due to a DNA conformational change induced by monoadduct accumulation that facilitates crosslink formation. This narrow dose-dependent transition could contribute to the narrow therapeutic window of BUS.
Morales-Ramírez
Pedro
P
Instituto Nacional de Investigaciones Nucleares, Mexico, DF, Mexico. pmr@nuclear.inin.mx
Miranda-Pasaye
Sindy
S
Cruz-Vallejo
Virginia L
VL
Vallarino-Kelly
Teresita
T
Mendiola-Cruz
María T
MT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D002066:Busulfan