title: BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity.
abstract: 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.
authors.affiliation: N-Gene R&D, Szent Istvan Krt. 18, Budapest, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Racz
authors.forename: Kalman
authors.initials: K
authors.lastname: Tory
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Berente
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Osz
authors.forename: Laszlo
authors.initials: L
authors.lastname: Jaszlits
authors.forename: Sandor
authors.initials: S
authors.lastname: Bernath
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Rabloczky
authors.forename: Peter
authors.initials: P
authors.lastname: Literati-Nagy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants; D002945:Cisplatin / Q000009:adverse effects*; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D010091:Oximes / Q000494:pharmacology*; D010758:Phosphorus / Q000378:metabolism; D010759:Phosphorus Isotopes; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D010091:Oximes; D010759:Phosphorus Isotopes; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D010758:Phosphorus; D002945:Cisplatin; C405586:BGP 15