PO.ET06.04 · 实验与分子治疗

OXTR靶向局部治疗可能是胸膜间皮瘤的一种有前景的策略

OXTR targeted local therapy could be a promising strategy for pleural mesothelioma

编号 3004 展板 26 时间 4/20 02:00–05:00 区域 Section 13 主讲 Ichidai Tanaka, MD;PhD

分会场 Molecular Targets 1

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作者与单位 Authors & Affiliations

Ichidai Tanaka¹, Hideyuki Itoigawa¹, Kazumi Hori¹, Shoichiro Fukuda², Heng Huang¹, Haruka Takata², Taketo Kato¹, Mitsuo Sato¹, Yoshitaka Sekido³, Shinobu Shimizu¹, Tatsuhiro Ishida², Toyofumi Fengshi Yoshikawa¹, Makoto Ishii¹

¹Nagoya University Graduate School of Medicine, Nagoya, Japan,²Tokushima University, Tokushima, Japan,³Aichi Cancer Center, Nagoya, Japan

摘要 Abstract

中文摘要

引言间皮瘤是全球最具侵袭性的肿瘤之一，预后极差。我们此前发现，催产素受体（OXTR）在间皮瘤中高表达，且OXTR敲低通过扰乱肿瘤细胞周期显著降低了高OXTR表达间皮瘤细胞的增殖。此外，OXTR抑制剂cligosiban在体内展现出抗肿瘤疗效。然而，全身给药需要高剂量，引发了对全身毒性的担忧。因此，我们探索了使用胸腔内药物递送的局部治疗策略，并开发了cligosiban的溶解制剂以增强药物蓄积。方法为建立通过经胸给药实现对胸膜间皮瘤局部控制的治疗方法，在几种间皮瘤细胞系中评估了溶于乙酰丙酸的cligosiban的抗肿瘤效果。对于体内分析，用裸鼠建立了胸腔内间皮瘤异种移植模型，并检验了胸腔内给予溶解型cligosiban的治疗疗效。结果在体外，两种高OXTR表达间皮瘤细胞系的剂量反应实验证明，在微摩尔浓度下细胞活力发生显著的浓度依赖性变化。同时，溶解型cligosiban显著降低了两种OXTR高表达间皮瘤细胞系中细胞周期调控基因的表达，包括细胞周期蛋白依赖性激酶1（Cyclin-dependent kinase 1）和Cyclin E2。在通过向裸鼠胸腔内注射高OXTR表达间皮瘤细胞建立的原位Y-MESO-27模型中，进行了50-400 µM溶解型cligosiban的胸腔内给药。每隔一天给予100 µM明显抑制了肿瘤生长，并证明了统计学上显著的生存延长。在胸腔内MSTO-211H模型（低OXTR表达间皮瘤细胞）中观察到类似趋势。接下来，我们将Alzet渗透泵植入小鼠皮下组织，并向小鼠胸腔连续给予总计400 µL（100 µM）的溶解型cligosiban。以1 µl/hr的注射速率，溶解型cligosiban显著延长了小鼠生存期。结论胸腔内给予溶解型cligosiban有效抑制间皮瘤进展，这是OXTR靶向局部治疗作为胸膜间皮瘤有前景策略的首次证明。

查看英文原文 English abstract

Introduction Mesothelioma is one of the most aggressive neoplasms worldwide and has an extremely poor prognosis. We have previously discovered that oxytocin receptors (OXTR) are highly expressed in mesothelioma and OXTR knockdown significantly decreases the proliferation of mesothelioma cells with high- OXTR expression by disturbing the tumor cell cycle. Furthermore, the OXTR inhibitor, cligosiban, demonstrated antitumor efficacy in vivo. However, systemic administration required high doses, raising concerns about systemic toxicity. Therefore, we explored a local treatment strategy using intrathoracic drug delivery, and developed a dissolved formulation of cligosiban to enhance drug accumulation. Methods To establish a treatment method for localized control via trans-thoracic administration against pleural mesothelioma, the antitumor effect of a dissolved cligosiban in levulinic acid was evaluated in several mesothelioma cell lines. For in vivo analysis, an intrathoracic mesothelioma xenograft model was established with nude mice, and the therapeutic efficacy of intrathoracic administration of the dissolved cligosiban was examined. Results In vitro, dose-response experiments in two mesothelioma cell lines with high- OXTR expression demonstrated significant concentration-dependent changes in cell viability at micromolar concentrations. In parallel, the dissolved cligosiban significantly decreased the expression of cell-cycle-regulatory genes, including Cyclin-dependent kinase 1 and Cyclin E2 in the two mesothelioma cell lines with OXTR -high expression. In an orthotopic Y-MESO-27 model established by intrathoracic injection of mesothelioma cells with high- OXTR expression into nude mice, intrathoracic administration of the dissolved cligosiban at 50-400 µM was performed. Administration at 100 µM every other day clearly suppressed tumor growth and demonstrated a statistically significant prolongation of survival. Similar trends were observed in an intrathoracic MSTO-211H model, which is mesothelioma cells with low- OXTR expression. Next, we implanted the Alzet osmotic pump into the mice subcutaneous tissue and continuously administered total 400 μL (100 µM) of the dissolved cligosiban into the mice thoracic cavity. With injection rate at 1μl/hr, the dissolved cligosiban significantly prolonged mice survival. Conclusion Intrathoracic administration of the dissolved cligosiban effectively suppresses mesothelioma progression, representing the first demonstration of OXTR-targeted local therapy as a promising strategy for pleural mesothelioma.

利益披露 Disclosure

I. Tanaka, None.. H. Itoigawa, None.. K. Hori, None.. S. Fukuda, None.. H. Huang, None.. H. Takata, None.. T. Kato, None.. M. Sato, None.. S. Shimizu, None. T. F. Yoshikawa, Nipro Co. ). Fujifilm Co. ). M. Ishii, Nippon Boehringer Ingelheim Co., Ltd. ). AstraZeneca K.K. ). Boehringer Ingelheim ). Pfizer Inc; Astellas Pharma Inc ). Ono Pharmaceutical Co. ). Shionogi & Co. ). AstraZeneca ). Sanofi KK ). Teijin Limited ). MSD KK ). Meiji Seika Pharma Co. ). Daiichi Sankyo Company, Limited ). GlaxoSmithKline KK ). Otsuka Pharmaceutical Co. ). KYORIN Pharmaceutical Co., Ltd. ). Sumitomo Dainippon Pharma Co. ). Novartis Pharma KK ). Kyowa Hakko Kirin Co. ). Eli Lilly Japan KK ). Chugai Pharmaceutical Co. ).

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