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 language | English (US) |
|---|---|
| Pages (from-to) | 2257-2260 |
| Number of pages | 4 |
| Journal | Cancer Research |
| Volume | 52 |
| Issue number | 8 |
| State | Published - Apr 15 1992 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Time dependence of the selective modulation of cisplatin-induced nephrotoxicity by WR2721 in the mouse
AU - Treskes, Marco
AU - Boven, Epie
AU - Holwerda, Ulbe
AU - Pinedo, Herbert M.
AU - Van Der Vijgh, Wim J F
PY - 1992/4/15
Y1 - 1992/4/15
N2 - 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.
AB - 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.
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M3 - Article
VL - 52
SP - 2257
EP - 2260
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 8
ER -