The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney hist
opathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP were
studied in rats, dFdC was administered intraperitoneally (i.p.) at single
doses of 90 mg kg(-1) while CDDP was administered i.p. at single doses of 6
mg kg(-1). Both drugs were injected either alone or sequentially in combin
ation. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other cas
e, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration
, the nephrotoxicity was manifested biochemically by elevation of serum cre
atinine, blood urea nitrogen and an increase in the kidney weight as a perc
entage of total body weight. In addition, marked decreases in serum albumin
and calcium levels were observed. Lipid peroxidation in the kidney was mon
itored by measuring the malondialdehyde (MDA) production level and kidney g
lutathione (GSH) content, which were increased and depleted, respectively.
Administration of dFdC 4 h and 24 h after CDDP administration did not signi
ficantly change the indices of CDDP-induced nephrotoxicity or the kidney pl
atinum concentration levels in comparison with those animals treated with C
DDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CD
DP administration significantly aggravated CDDP-induced nephrotoxicity whic
h was manifested by severe increases in the serum creatinine and blood urea
nitrogen levels as well as kidney weight as a percentage of total body wei
ght. In addition, kidney tissue showed severe GSH depletion and increases i
n the MDA production and platinum concentration levels. Moreover, treatment
of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of
CDDP-induced nephrotoxicity in comparison with those animals treated with d
FdC 4 h prior to CDDP. Histopathological examination demonstrated tubular a
trophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treat
ed group. However, pretreatment of rats with dFdC 4 h and 24 h Frier to CDD
P revealed extensive interstitial nephritis, renal tubular atrophy and tubu
lar necrosis with 'sloughing off' of the lining cells, especially with thos
e rats treated with dFdC 24 h prior to CDDP. These results might suggest th
at administration of dFdC prior to CDDP enhanced the lipid peroxidation in
kidney tissue and aggravated CDDP-induced nephrotoxicity. (C) 2001 Academic
Press.