ENHANCED FORMATION OF REACTIVE SPECIES FROM AMMINE-(1,1-CYCLOBUTANEDICARBOXYLATO)-PLATINUM(II) (CARBOPLATIN) IN THE PRESENCE OF OXYGEN-FREERADICALS

Citation
M. Tonetti et al., ENHANCED FORMATION OF REACTIVE SPECIES FROM AMMINE-(1,1-CYCLOBUTANEDICARBOXYLATO)-PLATINUM(II) (CARBOPLATIN) IN THE PRESENCE OF OXYGEN-FREERADICALS, Biochemical pharmacology, 46(8), 1993, pp. 1377-1383
Citations number
38
Categorie Soggetti
Pharmacology & Pharmacy",Biology
Journal title
ISSN journal
00062952
Volume
46
Issue
8
Year of publication
1993
Pages
1377 - 1383
Database
ISI
SICI code
0006-2952(1993)46:8<1377:EFORSF>2.0.ZU;2-S
Abstract
Experiments were designed to investigate the influence of oxygen free radicals on the rate of conversion of the anticancer drug iammine-(1,1 -cyclobutanedicarboxylato)platinum(II) (CBDCA) to reactive species abl e to bind to DNA. A system containing the Fe-EDTA chelate and ascorbat e was used to generate free radicals. The rate of drug conversion to b y-products, during incubation in chloride-free phosphate buffer at 37- degrees, was determined by HPLC analysis and found to be approximately 10 times faster in the presence of the free radical generating system , compared to CBDCA alone. The hydroxyl radical scavenger, mannitol, w as able to reduce the rate of CBDCA conversion significantly, while an enhancing effect was observed in the presence of superoxide dismutase . The platinum containing species, which are formed in the presence of free radicals, were demonstrated to react with isolated salmon sperm DNA. The rate of platinum binding to DNA during incubation of CBDCA in the presence of the Fe-EDTA/ascorbate system was markedly enhanced. N o effect on platinum binding to DNA during incubation with cis-diammin edichloroplatinum(II) (CDDP) in the same experimental conditions was o bserved, thus excluding an increased susceptibility of DNA itself to b inding of platinum, due to DNA damage induced by free radicals. These findings support the hypothesis that the increased conversion of CBDCA , previously observed in our laboratory, which occurs in the presence of hemoglobin could be mediated by a Fenton-like reaction resulting in oxygen free radical production, thus providing potential clues to imp rovements in the clinical use of this drug.