Kinetic of genotoxic expression in the pharmacodynamics of busulfan

Archives of Medical Research
P Morales-RamírezMaría T Mendiola-Cruz

Abstract

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. 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. 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. 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 the...Continue Reading

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Citations

Jul 11, 2016·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Nasrin Ghassemi-BarghiAbbas Jafarian Dehkordi
Jul 12, 2017·Journal of Applied Toxicology : JAT·Jacky Bhagat
Oct 25, 2016·Toxicology Mechanisms and Methods·Nasrin Ghassemi-BarghiAbbas Jafarian-Dehkordi
Sep 28, 2007·Environmental and Molecular Mutagenesis·Pedro Morales-Ramírez, Francisco González-Beltrán
Aug 23, 2017·Metabolomics : Official Journal of the Metabolomic Society·Yvonne S LinJeannine S McCune

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