This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Treskes, M. Articles by van der Vijgh, W. J. F. Search for Related Content PubMed PubMed Citation Articles by Treskes, M. Articles by van der Vijgh, W. J. F.

Time Dependence of the Selective Modulation of Cisplatin-induced Nephrotoxicity by WR2721 in the Mouse¹

Department of Oncology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

2-(3-Aminopropyiamino)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.

¹ This work was supported by the Dutch Cancer Society (Grant IKA 87-12) and U.S. Bioscience.

² To whom requests for reprints should be addressed.

Received 9/23/91. Accepted 2/ 7/92.

This article has been cited by other articles:

				O. Pluquet, S. North, A. Bhoumik, K. Dimas, Z.'e. Ronai, and P. Hainaut The Cytoprotective Aminothiol WR1065 Activates p53 through a Non-genotoxic Signaling Pathway Involving c-Jun N-terminal Kinase J. Biol. Chem., March 28, 2003; 278(14): 11879 - 11887. [Abstract] [Full Text] [PDF]

				K. Gelmon, E. Eisenhauer, C. Bryce, A. Tolcher, L. Mayer, E. Tomlinson, B. Zee, M. Blackstein, E. Tomiak, J. Yau, et al. Randomized Phase II Study of High-Dose Paclitaxel With or Without Amifostine in Patients With Metastatic Breast Cancer J. Clin. Oncol., October 1, 1999; 17(10): 3038 - 3047. [Abstract] [Full Text] [PDF]

				K. J. Weichert-Jacobsen, A. Bannowski, F. Kuppers, T. Loch, and M. Stockle Direct Amifostine Effect on Renal Tubule Cells in Rats Cancer Res., July 1, 1999; 59(14): 3451 - 3453. [Abstract] [Full Text] [PDF]

				M. Summerhayes Review : Amifostine and other chemoprotective agents in cancer chemotherapy: A brief review Journal of Oncology Pharmacy Practice, December 1, 1995; 1(4): 21 - 31. [Abstract] [PDF]