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.
Ma
J
J
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
Verweij
J
J
Planting
A S
AS
Kolker
H J
HJ
Loos
W J
WJ
de Boer-Dennert
M
M
van der Burg
M E
ME
Stoter
G
G
Schellens
J H
JH
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