BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity.
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.
Racz
Ildiko
I
N-Gene R&D, Szent Istvan Krt. 18, Budapest, Hungary.
Tory
Kalman
K
Gallyas
Ferenc
F
Berente
Zoltán
Z
Osz
Erzsebet
E
Jaszlits
Laszlo
L
Bernath
Sandor
S
Sumegi
Balazs
B
Rabloczky
Gyorgy
G
Literati-Nagy
Peter
P
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
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