Activity of docetaxel in paclitaxel-resistant ovarian cancer cells.

Abstract

PURPOSE:

The aim of this study was to determine the behavior of docetaxel (DTX) in ovarian cancer cells resistant to paclitaxel (PTX).

METHODS:

We used human ovarian adenocarcinoma cell lines KF, KFTx (PTX-resistant KF), SK-OV-3, and HAC-2. The sensitivity of the cells to PTX or DTX was determined by the MTT assay. Cellular accumulation of PTX and DTX was measured by high-performance liquid chromatography. mRNA of MDR-1 was detected by RT-PCR. Cell cycle distribution was determined by flow cytometry after exposure to the IC(50) of each drug. Bcl-2 phosphorylation was determined by Western blot analysis. Activity for tubulin polymerization of each drug was examined by a beta-tubulin polymerization assay.

RESULTS:

KFTx cells had a 5.5-fold greater resistance to PTX and a 7.3-fold greater resistance to DTX than KF cells, indicating that KFTx cells had acquired cross-resistance to DTX. SK-OV-3 cells were sensitive and HAC-2 cells were resistant to both PTX and DTX. The gene expression of MDR-1 increased after exposure to DTX in KF and KFTx cells. Residual cellular accumulation of PTX and DTX was significantly lower in KFTx cells than in KF cells. In contrast, MDR-1 expression was not detected in SK-OV-3 and HAC-2 cells. Flow cytometric analysis indicated no differences in alterations of cell cycle distribution following exposure to the two drugs. Bcl-2 phosphorylation occurred after exposure to DTX at a concentration equivalent to the clinical dose, but did not occur after exposure to PTX in KFTx cells. In HAC-2 cells, Bcl-2 phosphorylation was not detected after exposure to DTX or PTX at concentrations equivalent to the clinical doses. DTX showed greater tubulin polymerization activity than PTX in KFTx cells. beta-tubulin polymerization did not correlate with the concentration of PTX or DTX, suggesting that alteration in the tubulin reaction might contribute to the resistance in HAC-2 cells.

CONCLUSIONS:

The present study suggests that the mechanisms involved in cytotoxicity of and resistance to PTX and DTX do not differ, but DTX has a greater cytotoxic potential in PTX-resistant cells with an efflux system.

• Authors: Shinya Sato, Junzo Kigawa, Yasunobu Kanamori, Hiroaki Itamochi, Tetsuro Oishi, Muneaki Shimada, Takahiro Iba, Jun Naniwa, Kazunori Uegaki, Naoki Terakawa
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 53 Issue 3 Pg. 247-52 (Mar 2004) ISSN: 0344-5704 [Print] Germany
• PMID: 14610615 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Taxoids
• Tubulin
• Docetaxel
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Antineoplastic Agents, Phytogenic (metabolism, therapeutic use, toxicity)
• Biological Transport
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Docetaxel
• Drug Resistance, Neoplasm
• Female
• Humans
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• Paclitaxel (metabolism, therapeutic use, toxicity)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Messenger (metabolism)
• Taxoids (metabolism, therapeutic use, toxicity)
• Tubulin (metabolism)