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Combination Treatment With Trabectedin and Irinotecan or Topotecan Has Synergistic Effects Against Ovarian Clear Cell Carcinoma Cells
  1. Mahiru Kawano, MD*,
  2. Seiji Mabuchi, MD, PhD*,
  3. Toshiko Kishimoto, MD*,
  4. Takeshi Hisamatsu, MD, PhD*,
  5. Yuri Matsumoto, MD*,
  6. Tomoyuki Sasano, MD*,
  7. Ryoko Takahashi, MD*,
  8. Kenjiro Sawada, MD, PhD*,
  9. Kazuhiro Takahashi, MD, PhD,
  10. Toshifumi Takahashi, MD, PhD,
  11. Toshimitsu Hamasaki, PhD and
  12. Tadashi Kimura, MD, PhD*
  1. *Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka;
  2. Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata; and
  3. Department of Biomedical Statistics, Osaka University Graduate School of Medicine, Osaka, Japan.
  1. 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{at}


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.

  • Ovarian clear cell carcinoma
  • Trabectedin
  • Irinotecan
  • Topotecan
  • Isobologram

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  • 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.