Docetaxel and paclitaxel inhibit DNA-adduct formation and intracellular accumulation of cisplatin in human leukocytes.
The purpose of this study was to determine the mechanism of the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin. Cisplatin-induced DNA-adducts and cisplatin accumulation were quantitated in peripheral blood leukocytes (WBC). The WBC were obtained from patients treated with docetaxel or paclitaxel in phase I/II studies and were incubated in vitro with cisplatin. In addition, blank whole-blood samples were obtained from patients and healthy subjects and incubated in intro with cisplatin or docetaxel/paclitaxel and cisplatin. The cisplatin-induced DNA-adduct levels measured in WBC after treatment with docetaxel or paclitaxel were significantly lower than those determined in non-pretreated WBC. Docetaxel and paclitaxel reduced the intracellular accumulation of cisplatin in WBC by 46-47%. If the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin also occurs in other normal tissues such as bone marrow, it may well contribute to the sequence dependent toxicity that has been observed in clinical studies.
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
J
J
Ma
J
J
Verweij
A S
AS
Planting
H J
HJ
Kolker
W J
WJ
Loos
M
M
de Boer-Dennert
M E
ME
van der Burg
G
G
Stoter
J H
JH
Schellens
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics*; D018736:DNA Adducts / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043823:Taxoids
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018736:DNA Adducts; D004273:DNA, Neoplasm; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel; D002945:Cisplatin