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首页> 外文期刊>International Journal of Radiation Biology: Covering the Physical, Chemical, Biological, and Medical Effects of Ionizing and Non-ionizing Radiations >Farnesyltransferase inhibitors as radiation sensitizers.
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Farnesyltransferase inhibitors as radiation sensitizers.

机译：法呢基转移酶抑制剂作为辐射敏化剂。

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摘要

PURPOSE: The inhibition of activated Ras combined with radiotherapy was identified as a potential method for radiosensitization. MATERIALS AND METHODS: Immunoblotting was used to control for prenylation inhibition of the respective Ras isoforms and for changes in activity of downstream proteins. Clonogenic assays with human and rodent tumour cell lines and transfected cell lines served for the testing of radiosensitivity. Xenograft tumours were treated with farnesyl transferase inhibitors and radiation and assayed for ex vivo plating efficiency, regrowth of tumours and EF5 staining for detection of hypoxia. Concurrent treatment with L-778,123 and radiotherapy was performed in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) patients. RESULTS: Blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signalling resulted in radiation sensitization in in vitro and in vivo. The PI3 kinase downstream pathway was identified as a contributor to Ras-mediated radiation resistance. Additionally, increased oxygenation of xenograft tumours was observed after FTI treatment. Combined treatment in a phase I study was safe and effective in NSCLC and HNC. CONCLUSIONS: Tumour cells with activated Ras were sensitized to radiation. Unravelling the underlying mechanisms promises to lead to even more specific drugs with higher potency and safety.
机译：目的：结合放射疗法抑制激活的Ras被确定为潜在的放射增敏方法。材料与方法：免疫印迹法被用来控制相应Ras亚型的烯丙基化抑制和下游蛋白活性的变化。用人和啮齿动物的肿瘤细胞系和转染的细胞系进行的克隆试验可用于放射敏感性的测试。用法呢基转移酶抑制剂和放射线治疗异种移植肿瘤，并测定离体接种效率，肿瘤的再生长和EF5染色以检测缺氧。非小细胞肺癌（NSCLC）和头颈癌（HNC）患者同时进行L-778,123和放射疗法治疗。结果：通过突变或受体信号激活的Ras阻断了Ras蛋白在细胞系中的异戊二烯化作用，从而在体内外产生了辐射致敏作用。 PI3激酶下游通路被确定为Ras介导的辐射抗性的贡献者。另外，在FTI治疗后观察到异种移植肿瘤的氧合增加。一期研究的联合治疗在NSCLC和HNC中是安全有效的。结论：激活Ras的肿瘤细胞对放射线敏感。揭示潜在的机制有望导致具有更高效力和安全性的甚至更具体的药物。

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