Nephrotoxicity is one of the major dose limiting side effects of
cisplatin chemotherapy. The antitumor and toxic effects are mediated in part by different mechanisms, thus, permitting a selective inhibition of certain side effects. The influence of
O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) - a
poly(ADP-ribose) polymerase (
PARP) inhibitor - on the nephrotoxicity and antitumor efficacy of
cisplatin has been evaluated in experimental models.
BGP-15 either blocked or significantly reduced (60-90% in 100-200 mg/kg oral dose)
cisplatin induced increase in serum
urea and
creatinine level in mice and rats and prevented the structural degeneration of the kidney, as well. The nephroprotective effect of
BGP-15 treatment was revealed also in living mice by MRI analysis manifesting in the lack of oedema which otherwise developed as a result of
cisplatin treatment. The protective effect was accompanied by inhibition of
cisplatin-induced poly-ADP-ribosylation and by the restoration of the disturbed energy metabolism. The preservation of
ATP level in the kidney was demonstrated in vivo by localized NMR spectroscopy.
BGP-15 decreased
cisplatin-induced ROS production in rat kidney mitochondria and improved the
antioxidant status of the kidney in mice with
cisplatin-induced nephropathy. In rat kidney,
cisplatin caused a decrease in the level of Bcl-x, a mitochondrial protective
protein, and this was normalized by
BGP-15 treatment. On the other hand,
BGP-15 did not inhibit the antitumor efficacy of
cisplatin in cell culture and in transplantable solid
tumors of mice. Treatment with
BGP-15 increased the mean survival time of
cisplatin-treated P-388
leukemia bearing mice from 13 to 19 days.
PARP inhibitors have been demonstrated to diminish the consequences of
free radical-induced damage, and this is related to the chemoprotective effect of
BGP-15, a novel
PARP inhibitor. Based on these results, we propose that
BGP-15 represents a novel, non-
thiol chemoprotective agent.