Title
Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice
Author
Centraal Instituut voor Voedingsonderzoek TNO
Korst, A.E.C.
Boven, E.
van der Sterre, M.L.T.
Fichtinger-Schepman, A.M.J.
van der Vijgh, W.J.F.
Publication year
1997
Abstract
We have previously reported that amifostine potentiates the anti-tumour activity of carboplatin in mice. The present study was carried out in well-established human ovarian cancer xenografts OVCAR-3, A2780 and FMa grown subcutaneously in the nude mouse. It was found that a single dose of amifostine resulted in a higher increase in the anti-tumour activity of carboplatin than three doses of amifostine. A single dose of amifostine increased the AUC (area under the curve) values of total platinum in plasma ultrafiltrate (30.1 vs 18.2 uM x h), liver (307.7 vs 236.4 nmol g-1 x h), kidney (500.8 vs 368.3 nmol g-1 x h) and OVCAR-3 tumour tissue (184.0 vs 146.8 nmol g-1 x h). Despite this increase in total platinum, a decrease in platinum (Pt)-DNA adduct levels was observed in liver, kidney and bone marrow, which was significant in liver. In tumour tissue an insignificant increase in Pt-DNA adduct levels, specifically the Pt-GG adduct, was observed after treatment with a single dose of amifostine, which may explain the increase in anti-tumour activity. The increase in the AUC of total platinum was probably caused by a reduction in body temperature, which was most severe after three doses of amifostine. The extreme hypothermia may be the reason that three doses of amifostine resulted in less potentiation of the efficacy of carboplatin.
Subject
Amifostine
Anti-tumour activity
Carboplatin
Hypothermia
Pharmacokinetics
Amifostine
Animals
Antineoplastic Agents
Body Temperature
Carboplatin
DNA Adducts
Drug Administration Schedule
Drug Synergism
Female
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Ovarian Neoplasms
Platinum
Radiation-Protective Agents
Transplantation, Heterologous
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TNO identifier
233915
ISSN
0007-0920
Source
British Journal of Cancer, 75 (75), 1439-1446
Document type
article