BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity

Biochem Pharmacol. 2002 Mar 15;63(6):1099-111. doi: 10.1016/s0006-2952(01)00935-2.


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.

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antioxidants
  • Cisplatin / adverse effects*
  • Drug Interactions
  • Humans
  • Kidney / drug effects*
  • Kidney / metabolism
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Animal
  • Oximes / pharmacology*
  • Phosphorus / metabolism
  • Phosphorus Isotopes
  • Piperidines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Protective Agents / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Cells, Cultured
  • bcl-X Protein


  • Antineoplastic Agents
  • Antioxidants
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Oximes
  • Phosphorus Isotopes
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-X Protein
  • Phosphorus
  • Cisplatin
  • BGP 15