Abstract
The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.
Highlights
Ovarian carcinoma is the fourth most common cause of cancer death among women in the United States, with more than 21,880 new cases diagnosed and 13,850 deaths estimated to have occurred in 2010 [1].Clear cell carcinoma (CCC) of the ovary has been known to show poorer sensitivity to platinum-based frontline chemotherapy and to be associated with a worse prognosis than the more common serous adenocarcinoma
Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel
Trabectedin combined with everolimus may be more efficacious for the management of CCC
Summary
Ovarian carcinoma is the fourth most common cause of cancer death among women in the United States, with more than 21,880 new cases diagnosed and 13,850 deaths estimated to have occurred in 2010 [1]. Clear cell carcinoma (CCC) of the ovary has been known to show poorer sensitivity to platinum-based frontline chemotherapy and to be associated with a worse prognosis than the more common serous adenocarcinoma Authors' Affiliations: 1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka; and 2Department of Obstetrics and Gynecology, Yamagata University, School of Medicine, Yamagata, Japan. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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