Department of Gastroenterological Surgery and Surgical Oncology, Graduate School of Medicine Dentistry, Okayama University, Okayama, Japan.
Cancer Biol Ther. 2013 Mar;14(3):230-6. doi: 10.4161/cbt.23294. Epub 2013 Jan 4.
Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.
食管鳞状细胞癌（ESCC）仍然是预后最差的侵袭性癌症之一，尽管有一些报道表明，使用一些新的化疗药物可以提高治疗效果。最近的药物开发有助于提高对 mTOR 活性的抑制特异性，从而使许多类型的恶性肿瘤得以迅速进展。替西罗莫司（CCI-779，TricelTM）是雷帕霉素的一种新合成类似物，为肾细胞癌患者提供了更好的治疗效果。在这项研究中，我们通过评估靶向 mTOR 的替西罗莫司治疗 ESCC 的疗效，使用先进的 ESCC 动物模型评估其生存优势。首先，我们证实 58 例 ESCC 肿瘤组织中的 46 例（79.3%）磷酸化 mTOR 的表达增加，并且随着肿瘤的进展似乎得到了加强。本研究中使用的所有 ESCC 细胞系均显示 mTOR 磷酸化增加，同时缺氧诱导因子-1α（HIF-1α）上调，这是 mTOR 调控的关键效应物之一。替西罗莫司治疗明显抑制了 mTOR 及其下游效应物的激活，从而降低了 ESCC 细胞的增殖能力。最后，每周给予替西罗莫司治疗显著减小了裸鼠皮下肿瘤的大小（载体，3261.6 ± 722.0；替西罗莫司，599.2 ± 122.9；p = 0.007），并有效地延长了荷食管癌细胞的原位小鼠的存活时间（中位生存时间：对照组，31 天；替西罗莫司组，43 天；p = 0.0024）。这些数据表明，替西罗莫司靶向 mTOR 可能成为食管癌的一种治疗选择，有助于改善预后。
