Cellular efflux pump and interaction between cisplatin and paclitaxel in ovarian cancer cells.
OBJECTIVE
The aim of this study was to evaluate the combination effect of paclitaxel (PTX) and cisplatin (CDDP) and to determine the mechanisms of interaction between these agents.


RESULTS
We used human ovarian adenocarcinoma cell lines, namely a parent cell line (KF), a CDDP-resistant cell line (KFr) and a PTX-resistant cell line (KFTx).The combination effect of PTX and CDDP was synergistic on KF and KFTx and additive on KFr. The incidence of anaphase or telophase, evaluated by immunofluorescence microscopy, decreased with PTX and significantly decreased with PTX and CDDP in KF and KFTx. The concentration of PTX, which was measured by high-performance liquid chromatography, was higher in KF and KFTx cells treated with a combination of PTX and CDDP than those treated with PTX alone. Multidrug resistance gene mRNA appeared in KFTx and its expression decreased after exposure to PTX and CDDP. After exposure to CDDP, the expression of multidrug resistance-associated protein (MRP) and the concentration of glutathione increased in KF, but not in KFr or KFTx. MRP expression slightly increased in KF and KFTx after exposure to PTX. In contrast, its expression decreased in KFr.


CONCLUSIONS
The present study suggests that CDDP enhances PTX accumulation and that the interaction of these agents is synergistic in CDDP-sensitive cells.
Kamazawa
S
S
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.
Kigawa
J
J
Minagawa
Y
Y
Itamochi
H
H
Shimada
M
M
Takahashi
M
M
Sato
S
S
Akeshima
R
R
Terakawa
N
N
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D000705:Anaphase / Q000187:drug effects; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use; D017931:DNA Primers; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D013692:Telophase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D017239:Paclitaxel; D002945:Cisplatin