Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes.
Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes.
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发表时间：
1998-04
期刊：
影响因子：
11.2
通讯作者：
E. Bernhard;W. Mckenna;A. Hamilton;S. Sebti;Y. Qian;Junmin Wu;R. Muschel
中科院分区：
文献类型：
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作者：
E. Bernhard;W. Mckenna;A. Hamilton;S. Sebti;Y. Qian;Junmin Wu;R. Muschel
ras癌基因激活对肿瘤细胞辐射杀伤敏感性的影响一直是放射生物学中尚未解决的问题。我们已经研究了这个问题，通过测量的辐射敏感性的人肿瘤细胞系致癌突变的H-或K-ras基因治疗后，异戊二烯转移酶抑制剂，防止其活性所需的ras的翻译后修饰。使用两种措施的克隆生存，我们已经证明了放射增敏细胞系致癌H-ras突变或致癌K-ras突变时，ras加工被异戊二烯基转移酶抑制剂治疗抑制。相反，在表达野生型ras的细胞系中抑制ras加工对辐射诱导的细胞死亡没有影响。异戊烯基转移酶抑制剂本身抑制克隆生存在某些情况下，但这种抑制并不相关的ras突变状态。虽然异戊烯基转移酶抑制剂和放射治疗导致克隆形成比单独治疗野生型ras细胞更大的减少，但两种药物治疗对ras突变肿瘤细胞的细胞杀伤具有协同作用。我们的研究结果表明，在人类肿瘤细胞中的致癌ras活性的抑制可以减少这些细胞的辐射存活，这表明致癌ras可以有助于人类肿瘤的辐射抗性。这些结果进一步证明了使用异戊烯基转移酶抑制剂与放射疗法联合治疗人类恶性肿瘤的潜力。
The influence of activated ras oncogenes on the sensitivity of human tumor cells to killing by radiation has been an unresolved question in radiobiology. We have examined this question by measuring the radiation sensitivity of human tumor cell lines with oncogenic mutations in their H- or K-ras genes after treatment with prenyltransferase inhibitors that prevent the posttranslational modification of ras required for its activity. Using two measures of clonogenic survival, we have demonstrated radiosensitization in cell lines with oncogenic H-ras mutations or with oncogenic K-ras mutations when ras processing was inhibited by prenyltransferase inhibitor treatment. In contrast, the inhibition of ras processing in cell lines expressing wild-type ras had no effect on radiation-induced cell death. The prenyltransferase inhibitors themselves inhibited clonogenic survival in some cases, but this inhibition did not correlate with ras mutational status. Although treatment with prenyltransferase inhibitors and radiation resulted in a greater reduction of clonogenicity than either treatment alone in cells with wild-type ras, treatment with both agents had a synergistic effect on cell killing in tumor cells with ras mutations. Our results demonstrate that the inhibition of oncogenic ras activity in human tumor cells can reduce the radiation survival of these cells, suggesting that oncogenic ras can contribute to radiation resistance in human tumors. These results further demonstrate the potential of using prenyltransferase inhibitors in combination with radiotherapy in the treatment of human malignancies.