Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary.
Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary.
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DOI：
10.1371/journal.pone.0151050
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kimura T
中科院分区：
文献类型：
--
作者：
Takahashi R;Mabuchi S;Kawano M;Sasano T;Matsumoto Y;Kuroda H;Kozasa K;Hashimoto K;Sawada K;Kimura T
本研究的目的是评价lurbinectedin作为单一药物或与现有抗癌药物联合治疗卵巢透明细胞癌（CCC）的抗肿瘤作用，CCC被认为是一种侵袭性、耐药性、组织学亚型。使用人卵巢CCC细胞系，使用MTS测定评估lurbinectedin、SN-38、多柔比星、顺铂和紫杉醇作为单一药剂的抗肿瘤作用。然后，使用等效线图分析评价涉及lurbinectedin和其他4种药物中的1种的联合治疗的抗肿瘤作用，以检查这些组合是否显示协同作用。还使用顺铂耐药和紫杉醇耐药CCC亚系检查了每种治疗的抗肿瘤活性。最后，我们确定了mTORC 1抑制对基于lurbinectedin的化疗的抗肿瘤活性的影响。Lurbinectedin在体外对化疗敏感和耐药的CCC细胞具有显著的抗肿瘤活性。对小鼠CCC细胞异种移植物的检查显示lurbinectedin显著抑制肿瘤生长。在测试的组合中，lurbinectedin加SN-38导致显著的协同效应。该组合对顺铂耐药和紫杉醇耐药CCC细胞系也具有强的协同作用。依维莫司显著增强了基于lurbinectedin的化疗的抗肿瘤活性。Lurbinectedin是一种靶向主动转录的新药，在CCC中作为单药使用时表现出抗肿瘤活性，与伊立替康联合使用时具有协同抗肿瘤作用。我们的研究结果表明，lurbinectedin是一种有前途的药物治疗卵巢CCC，作为一线治疗和作为补救治疗复发性病变后，发展铂类或紫杉醇治疗。
The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment.