Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Int J Gynecol Cancer. 2013 Sep;23(7):1210-8. doi: 10.1097/IGC.0b013e31829d2d51.
Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR-hypoxia-induced factor (HIF) signal transduction system.
Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor-treated condition were analyzed.
Mammalian target of rapamycin-HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor-treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents-only group.
Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.
在将哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂（雷帕霉素和依维莫司）与其他抗癌药物联合用于临床试验之前，本研究旨在证实针对卵巢透明细胞腺癌（CCA）的新治疗策略的疗效，该策略针对 mTOR-缺氧诱导因子（HIF）信号转导系统。
使用 CCA 的培养细胞和动物模型，分析 mTOR 抑制剂处理条件下 mTOR-HIF 共因子的改变和细胞增殖。
mTOR 抑制剂依赖性地抑制 mTOR-HIF 共因子，导致培养的 CCA 增殖受到抑制。然而，von Hippel-Lindau 在信使 RNA 水平上上调。在皮下植入 CCA 细胞的裸鼠中，mTOR 抑制剂治疗组比未治疗组更明显地在肿瘤中心周围检测到细胞凋亡和坏死。在评估与其他抗肿瘤药物联合治疗时，与仅用化疗药物组相比，mTOR 抑制剂联合化疗药物治疗显著减小了肿瘤体积。
mTOR 抑制剂治疗有望作为一种新的治疗策略下调 CCA 的细胞增殖。
