Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Cancer Sci. 2011 Jul;102(7):1344-9. doi: 10.1111/j.1349-7006.2011.01967.x. Epub 2011 Jun 2.
Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.
替西罗莫司（CCI-779）是一种最近合成的雷帕霉素类似物，特异性抑制 mTOR，并已被批准用于肾细胞癌的临床治疗。最近的报告表明，替西罗莫司在一些癌症中具有生长抑制作用，包括非小细胞肺癌（NSCLC）。在这项研究中，我们旨在探讨替西罗莫司作为 NSCLC 治疗药物的潜在治疗用途。使用培养的 NSCLC 细胞（A549、H1299 和 H358），我们确定了替西罗莫司对细胞增殖的影响及其对皮下肿瘤的抗肿瘤作用，以及对模拟晚期 NSCLC 的癌细胞胸膜播散的小鼠生存的贡献。替西罗莫司以剂量依赖的方式抑制 NSCLC 细胞的增殖，IC50<1 nM。Western blot 分析显示，替西罗莫司治疗在 1 小时内特异性抑制 mTOR 及其下游效应物的磷酸化，同时伴有 G0/G1 期细胞群体增加，但根据流式细胞术，亚 G0 期细胞群体没有增加。当 NSCLC 皮下荷瘤小鼠用替西罗莫司治疗时，肿瘤体积明显减小（第 35 天肿瘤体积：载体组与替西罗莫司组=1239 与 698 cm3；P<0.05）。此外，在胸膜播散性荷瘤小鼠中用替西罗莫司治疗时观察到生存期延长（中位生存期：载体组与替西罗莫司组=53.5 与 72.5 天；P<0.05）。这些结果表明，替西罗莫司由于其抗增殖作用，可能对 NSCLC 的治疗有用，并且可能是晚期 NSCLC 的潜在治疗方法，可延长生存时间。
