Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse.

Abstract

2-(3-Aminopropylamino)ethylphosphorothioic acid (WR2721; ethiofos) was shown to selectively protect nontumor tissues from cis-diamminedichloroplatinum(II) (cisplatin)-induced toxicity, when administered 30 min prior to the platinum drug. Selectivity of protection by WR2721 is probably due to the preferential formation and uptake of the thiol metabolite 2-(3-aminopropylamino)ethanethiol (WR1065), which can inactivate toxic platinum-species inside the cell. We investigated the protective potential of WR2721, when administered at different time points relative to cisplatin. BALB/c mice treated with WR2721 (200 mg/kg i.p.) either 30 min or 5 min prior to cisplatin (i.p.) allowed a 2.2-fold increase in cisplatin dose to 19 mg/kg before the occurrence of nephrotoxicity as expressed by an increase in plasma urea. A small part of the protection could be ascribed to the mannitol (200 mg/kg), present in the formulated WR2721. WR2721 (200 mg/kg) 30 min after 14.5-16-mg/kg cisplatin did not offer any protection against the rise in plasma urea. WR2721 (200 mg/kg) 5 min before 19-mg/kg cisplatin did not cause liver toxicity (increase in serum glutamic pyruvic transaminase or serum glutamic oxaloacetic transaminase). Furthermore, WR2721 (200 mg/kg) 5 min prior to cisplatin did not reduce antitumor activity in nude mice bearing well-established human ovarian cancer xenografts. Under protection of WR2721, the dose of cisplatin could be increased by a factor of 1.6 to 8 mg/kg (administered twice weekly), resulting in an increased antitumor activity.