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Combination Treatment With Trabectedin and Irinotecan or Topotecan Has Synergistic Effects Against Ovarian Clear Cell Carcinoma Cells

Kawano, Mahiru MD*; Mabuchi, Seiji MD, PhD*; Kishimoto, Toshiko MD*; Hisamatsu, Takeshi MD, PhD*; Matsumoto, Yuri MD*; Sasano, Tomoyuki MD*; Takahashi, Ryoko MD*; Sawada, Kenjiro MD, PhD*; Takahashi, Kazuhiro MD, PhD; Takahashi, Toshifumi MD, PhD; Hamasaki, Toshimitsu PhD; Kimura, Tadashi MD, PhD*

International Journal of Gynecological Cancer: June 2014 - Volume 24 - Issue 5 - p 829–837
doi: 10.1097/IGC.0000000000000143
Basic Science

Objectives: The objective of this study was to investigate the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype.

Methods: Using 4 human CCC cell lines (RMG1, RMG2, KOC7C, and HAC2), the cytotoxicities of trabectedin, SN-38, topotecan, doxorubicin, cisplatin, and paclitaxel as single agents were first assessed using the MTS assay. Then, the cytotoxicities of combination treatments involving trabectedin and 1 of the other 4 agents were evaluated by isobologram analysis to examine whether these combinations displayed synergistic, additive, or antagonistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines, which were derived from the parental CCC cells by continuously exposing them to cisplatin or paclitaxel. Finally, we determined the effect of everolimus on the antitumor efficacy of trabectedin-based combination chemotherapy.

Results: Concurrent exposure to trabectedin and SN-38 or topotecan resulted in synergistic interactions in all 4 CCC cell lines. Among the tested combinations, trabectedin plus SN-38 was the most effective cytotoxic regimen. The combination of trabectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of trabectedin plus SN-38 or topotecan.

Conclusions: Combination treatment with trabectedin and SN-38 displays the greatest cytotoxic effect against ovarian CCC. Our in vitro study provides the rationale for future clinical trials of trabectedin plus irinotecan with or without everolimus in patients with ovarian CCC in both the front-line chemotherapy setting and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel.

*Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka; †Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata; and ‡Department of Biomedical Statistics, Osaka University Graduate School of Medicine, Osaka, Japan.

Address correspondence and reprint requests to Seiji Mabuchi, MD, PhD, Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: smabuchi@gyne.med.osaka-u.ac.jp.

This study was supported in part by grants-in-aid for General Scientific Research no. 23592446 and 22390308 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

Received October 15, 2013

Accepted March 11, 2014

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.