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
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.