Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice.
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 microM 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.
Korst
A E
AE
University Hospital Vrije Universiteit, Department of Medical Oncology, Amsterdam, The Netherlands.
Boven
E
E
van der Sterre
M L
ML
Fichtinger-Schepman
A M
AM
van der Vijgh
W J
WJ
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001831:Body Temperature / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D018736:DNA Adducts / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010984:Platinum / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D018736:DNA Adducts; D011837:Radiation-Protective Agents; D010984:Platinum; D016190:Carboplatin; D004999:Amifostine