Combination treatment with trabectedin and irinotecan or topotecan has synergistic effects against ovarian clear cell carcinoma cells.
OBJECTIVE
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.
Mahiru
M
Kawano
Seiji
S
Mabuchi
Toshiko
T
Kishimoto
Takeshi
T
Hisamatsu
Yuri
Y
Matsumoto
Tomoyuki
T
Sasano
Ryoko
R
Takahashi
Kenjiro
K
Sawada
Kazuhiro
K
Takahashi
Toshifumi
T
Takahashi
Toshimitsu
T
Hamasaki
Tadashi
T
Kimura
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004149:Dioxoles / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D006801:Humans; D000077146:Irinotecan; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D000077606:Trabectedin; D014407:Tumor Cells, Cultured
D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077146:Irinotecan; D019772:Topotecan; D004317:Doxorubicin; D000068338:Everolimus; D000077606:Trabectedin; D017239:Paclitaxel; D002945:Cisplatin; D020123:Sirolimus; D002166:Camptothecin