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

Marco Treskes, Epie Boven, Ulbe Holwerda, Herbert M. Pinedo, Wim J F Van Der Vijgh

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2257-2260
Number of pages4
JournalCancer Research
Volume52
Issue number8
StatePublished - Apr 15 1992
Externally publishedYes

Fingerprint

Amifostine
Cisplatin
Platinum
Urea
Poisons
Mannitol
Aspartate Aminotransferases
Alanine Transaminase
Sulfhydryl Compounds
Heterografts
Nude Mice
Ovarian Neoplasms
Acids
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Treskes, M., Boven, E., Holwerda, U., Pinedo, H. M., & Van Der Vijgh, W. J. F. (1992). Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse. Cancer Research, 52(8), 2257-2260.

Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse. / Treskes, Marco; Boven, Epie; Holwerda, Ulbe; Pinedo, Herbert M.; Van Der Vijgh, Wim J F.

In: Cancer Research, Vol. 52, No. 8, 15.04.1992, p. 2257-2260.

Research output: Contribution to journalArticle

Treskes, M, Boven, E, Holwerda, U, Pinedo, HM & Van Der Vijgh, WJF 1992, 'Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse', Cancer Research, vol. 52, no. 8, pp. 2257-2260.
Treskes M, Boven E, Holwerda U, Pinedo HM, Van Der Vijgh WJF. Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse. Cancer Research. 1992 Apr 15;52(8):2257-2260.
Treskes, Marco ; Boven, Epie ; Holwerda, Ulbe ; Pinedo, Herbert M. ; Van Der Vijgh, Wim J F. / Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse. In: Cancer Research. 1992 ; Vol. 52, No. 8. pp. 2257-2260.
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