The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary
The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary
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DOI：
10.1158/1078-0432.ccr-10-2987
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发表时间：
2011-07-01
影响因子：
11.5
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
--
作者：
Mabuchi, Seiji;Hisamatsu, Takeshi;Kimura, Tadashi
目的：本研究的目的是评估曲贝替定对卵巢透明细胞癌 (CCC) 的抗肿瘤功效，这种癌被认为是一种侵袭性、耐药性、组织学亚型。实验设计：使用 6 种人卵巢癌细胞系（3 种 CCC 和 3 种浆液性腺癌），在体外检查曲贝替定的抗肿瘤作用，并比较其活性 根据组织学。接下来，我们在体外检测了曲贝替定在顺铂耐药和紫杉醇耐药 CCC 细胞中的抗肿瘤活性。然后，使用接种 CCC 细胞系的小鼠评估曲贝替定的体内作用。使用 2 对曲贝替定敏感亲本和曲贝替定耐药 CCC 亚系，我们研究了 mTOR 在曲贝替定获得性耐药机制中的作用。最后，我们在体外和体内测定了依维莫司抑制mTOR对曲贝替定抗肿瘤功效的影响。结果：曲贝替定在体外对化疗敏感和化疗耐药的CCC细胞显示出显着的抗肿瘤活性。 CCC 细胞的小鼠异种移植表明曲贝替定显着抑制肿瘤生长。在曲贝替定耐药的 CCC 细胞中观察到 mTOR 的激活程度高于其各自的亲代细胞。 mTOR的持续抑制显着增强了曲贝替定的治疗效果，并阻止了CCC细胞对曲贝替定产生耐药性。结论：曲贝替定是一种很有前景的CCC药物，可作为一线化疗药物以及作为既往接受过顺铂或紫杉醇治疗的复发性CCC的二线治疗药物。此外，曲贝替定与依维莫司联合治疗 CCC 可能更有效。临床癌症研究； 17(13)； 4462-73。 (C) 2011 年 AACR。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusion: 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. Clin Cancer Res; 17(13); 4462-73. (C) 2011 AACR.