Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer.
OBJECTIVE
The objective of this study was to determine the relationship between multidrug resistance and sensitivity to paclitaxel (PTX) in ovarian cancer.


METHODS
We used human ovarian adenocarcinoma cell lines, KF, a PTX-resistant cell line (KFTx), SK-OV-3, and KOC7c. Additionally, 27 patients with ovarian cancer who had residual disease were examined. All patients underwent postoperative chemotherapy consisting of 175 mg/m(2) PTX and area under curve (AUC) 5 carboplatin. The sensitivity of the cells to PTX or cisplatin (CDDP) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. mRNA expression of multidrug resistance gene-1 (MDR-1) and multidrug resistance-associated protein-1 (MRP-1) and MRP-2 was determined by reverse transcription-polymerase chain reaction. beta-Tubulin polymerization and Bcl-2 phosphorylation were examined by Western blot analysis.


RESULTS
Compared with KF, the IC(50) to PTX was 5.5-fold higher for KFTx, 0.3-fold for SK-OV-3, and 52.1-fold for KOC7c. The IC(50) to CDDP was 0.7-, 4.2-, and 5.8-fold, respectively. Expression of the MDR-1 gene was clearly observed in KFTx and KOC7c. Expression of MRP-1 was observed in SK-OV-3 and KOC7c. Expression of MRP-2 was detected only in KOC7c. CDDP enhanced beta-tubulin polymerization induced by PTX in CDDP-sensitive cells. Bcl-2 phosphorylation appeared after exposure to IC(50) PTX in all cells. Twenty-one patients responded to chemotherapy and six did not. Expression of the MDR-1 gene for nonresponders was significantly higher than that for responders (260.0 +/- 191.6 vs 9.3 +/- 21.8). With the cutoff value of MDR-1 expression at 100, the predictive value for chemoresponse was 96%. Expression of the MRP-1 and MRP-2 genes did not differ between nonresponders and responders.


CONCLUSIONS
MDR-1 gene expression may be a useful predictor for PTX-based chemotherapy.
Kamazawa
Shunji
S
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, 683-8504, Japan.
Kigawa
Junzo
J
Kanamori
Yasunobu
Y
Itamochi
Hiroaki
H
Sato
Shinya
S
Iba
Takahiro
T
Terakawa
Naoki
N
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics*; D017239:Paclitaxel / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D012333:RNA, Messenger; C000715087:ABCC2 protein, human