Pharmacokinetics of cisplatin with and without amifostine in tumour-bearing nude mice

Amifostine (Ethyol, WR-2721) is in use in the clinic as a protector against platinum-induced toxicities. We have previously reported that amifostine induced a potentiation of the antitumour activity of carboplatin in human ovarian cancer xenografts. An influence of amifostine on the pharmacokinetics...

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Bibliographic Details
Published in:	European journal of cancer (1990) Vol. 34; no. 3; pp. 412 - 416
Main Authors:	Korst, A.E.C., Boven, E., van der Sterre, M.L.T., Fichtinger-Schepman, A.M.J., van der Vijgh, W.J.F.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-02-1998 Elsevier
Subjects:	amifostine Amifostine - administration & dosage Animals Antineoplastic agents Antineoplastic Agents - pharmacokinetics Biological and medical sciences Chemotherapy cisplatin Cisplatin - administration & dosage Cisplatin - pharmacokinetics Drug Combinations Drug Synergism ethyol Female Humans Kidney - metabolism Liver - metabolism Medical sciences Mice Neoplasm Transplantation Ovarian Neoplasms - metabolism pharmacokinetics Pharmacology. Drug treatments Platinum - analysis Radiation-Protective Agents - administration & dosage Transplantation, Heterologous WR-2721 ethyol pharmacokinetics amifostine WR-2721 cisplatin Antineoplastic agent Animal model Rodentia Case control study Malignant tumor Amifostine Cisplatin Vertebrata Chemotherapy Mammalia Mouse Animal Combined treatment Pharmacokinetics Platinum II Complexes
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Summary:	Amifostine (Ethyol, WR-2721) is in use in the clinic as a protector against platinum-induced toxicities. We have previously reported that amifostine induced a potentiation of the antitumour activity of carboplatin in human ovarian cancer xenografts. An influence of amifostine on the pharmacokinetics of carboplatin, resulting in higher platinum concentrations in plasma and tissues of the tumour-bearing nude mice, was thought to be the cause of enhancement of the antitumour activity. Therefore, the pharmacokinetics of cisplatin were investigated in tumour-bearing nude mice treated with cisplatin alone or in combination with amifostine. A significant increase in the area under the curve (AUC) of the total platinum concentration in mice treated with amifostine was only observed in the kidney (from 355 to 398nmolh/g), whereas in the other tissues and plasma no significant changes were measured. The selective protection of normal tissues by amifostine was confirmed by a decrease in the AUC of the cisplatin-DNA adduct levels in normal tissues. The decrease was only significant in the liver (282–240fmolh/μg DNA), whereas in tumour tissue a slight increase in the AUC of the cisplatin–DNA adducts could be detected (91.3–110.1fmolh/μg DNA). The minor influence of amifostine on the pharmacokinetics of cisplatin may be the reason why amifostine did not potentiate the antitumour activity of cisplatin. The influence of amifostine on cisplatin–DNA adduct levels in normal tissues versus tumour tissues is further evidence for the usefulness of this toxicity modulator in cancer patients.
ISSN:	0959-8049 1879-0852
DOI:	10.1016/S0959-8049(97)10012-0