The Cancer Research UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
Radiother Oncol. 2012 Jun;103(3):388-93. doi: 10.1016/j.radonc.2012.04.001. Epub 2012 Apr 30.
For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation.
Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels.
STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions.
This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.
对于诊断为晚期肾细胞癌（RCC）的患者，治疗选择很少。放射治疗主要用于治疗转移，并且在肾癌的辅助治疗中效果不佳。此外，RCC 对标准细胞毒性化学疗法具有抗性。靶向抗血管生成剂是 RCC 的标准治疗方法，但无法治愈。较新的药物，例如 mTOR 抑制剂和其他诱导自噬的药物，已显示出治疗 RCC 的巨大潜力。在这里，我们研究了小分子 STF-62247 调节辐射的潜在用途。
使用 RCC 细胞系，我们通过集落存活测定评估了对辐射以及诱导自噬性细胞死亡的药物的敏感性。此外，还在生理氧水平下对这些药物进行了测试。
STF-62247特异性诱导 VHL 缺失的细胞发生自噬性细胞死亡，VHL 是 RCC 发生的必需突变。STF-62247 处理不会改变细胞周期进程，但与辐射联合使用时，可在含氧和低氧/生理条件下增加细胞杀伤。
这项研究强调了将靶向治疗药物（例如 STF-62247 或替西罗莫司）与放射治疗相结合以减少对部分或全部肾切除术的依赖并改善患者预后的可能性。
