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 paclitaxelresistant 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.

ObjectiveTo investigate the utility of serum squamous cell carcinoma antigen (SCC-Ag) levels upon the diagnosis of recurrent cervical cancer for decision making in patient management.MethodsClinical records from 167 cervical cancer patients who developed recurrence between April 1996 and September 2010 were reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of serum SCC-Ag levels at the time of recurrence. The effects of various salvage treatments on survival outcomes of recurrent cervical cancer were examined with respect to serum SCC-Ag levels.ResultsSerum SCC-Ag levels were elevated (>2.0 ng/mL) in 125 patients (75%) when recurrence was diagnosed. These patients exhibited significantly shorter postrecurrence survival than those with normal SCC-Ag levels (log-rank; p=0.033). Multivariate analyses revealed that an elevated serum SCC-Ag level was an independent prognostic factor for poor postrecurrence survival. In patients with SCC-Ag levels <14.0 ng/mL, radiotherapy or surgery resulted in improved survival compared with chemotherapy or supportive care. In contrast, in patients with SCC-Ag levels of ≥14.0 ng/mL, salvage treatment with radiotherapy had only a minimal impact on postrecurrence survival.ConclusionThe serum SCC-Ag level measured when cervical cancer recurrence is diagnosed can be useful for deciding upon the appropriate salvage treatment.

The RhoA/Rho-kinase cascade is involved in various cellular functions, including migration, proliferation, and smooth muscle contraction. We examined the potential role of this pathway in oxytocin-induced uterine contraction. The specific Rho-kinase inhibitor Y-27632 inhibited oxytocin-induced rat uterine contraction on d 21 of pregnancy in a concentration-dependent manner, whereas the extent of this inhibition was reduced in the nonpregnant uterus. Y-27632 had no effect on oxytocin-induced intracellular Ca(2+) mobilization in myometrial cells. Immunoblot analysis showed that oxytocin increased the level of myosin light chain phosphorylation, and this increase was attenuated by Y-27632. Oxytocin increased the phosphorylation of myosin-binding subunit of myosin phosphatase, one of the major substrates of Rho-kinase, and this increase was reduced by Y-27632. The expression of Rho-kinase protein was shown to increase in the uterus during pregnancy compared with the nonpregnant uterus, whereas the expression of RhoA protein remained at the same level during pregnancy. RT-PCR and Northern blot analysis showed that the expression of Rho-kinase was up-regulated at the transcriptional level during pregnancy. These results suggest that the RhoA/Rho-kinase pathway may have an important role in oxytocin-induced uterine contraction, and that up-regulation of Rho-kinase is involved in the mechanism underlying the increased contractility of the pregnant myometrium.

Objectives:Lurbinectedin is a marine-derived covalent DNA minor groove binder and is structurally similar to trabectedin except for the C subunit. Lurbinectedin (PM01183) is a newly developed antitumor agent that is currently being investigated in phase I/II clinical trials in patients with solid tumors including ovarian cancer. The objective of this study is to investigate the effectiveness of lurbinectedin as a single agent or as combination with existing antitumor agent against ovarian clear cell carcinoma which is regarded as an aggressive chemoresistant histological subtype. Methods:Using human ovarian clear cell carcinoma cell lines, the anti-tumor effects of lurbinectedin, SN38, topotecan, doxorubicin, cisplatin and paclitaxel as single agent were assessed by MTS assay. Then the cytotoxicities of combination treatments involving lurbinectedin and 1 of the 4 agents were evaluated by isobologram analysis to examine which of these combinations displayed synergistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant ovarian clear cell carcinoma sublines, which were derived from the parental clear cell carcinoma cells by continuously exposing them to cisplatin or paclitaxel. Finally, using nude mice inoculated with clear cell carcinoma cells, we examined the growth-inhibitory effect of lurbinectedin in vivo. Results:Lurbinectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that lurbinectedin significantly inhibits tumor growth. Concurrent exposure to lurbinectedin and SN-38 resulted in synergistic interactions in CCC cell lines. The combination of lurbinectedin 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 single agent lurbinectedin and combination of lurbinectedin plus SN-38. Conclusions:Lurbinectedin 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, lurbinectedin combined with irinotecan may be more efficacious for the management of CCC. Citation Format: Ryoko Takahashi, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Hiromasa Kuroda, Katsumi Kozasa, Kenjirou Sawada, Tadashi Kimura. Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2015-1642