Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones.
Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones.
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DOI：
10.1073/pnas.95.4.1369
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发表时间：
1998-02
影响因子：
11.1
通讯作者：
M. Moasser;L. Sepp-Lorenzino;N. Kohl;A. Oliff;A. Balog;D. Su;S. Danishefsky;N. Rosen
中科院分区：
文献类型：
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作者：
M. Moasser;L. Sepp-Lorenzino;N. Kohl;A. Oliff;A. Balog;D. Su;S. Danishefsky;N. Rosen
一类重要的细胞蛋白，包括p21ras家族的成员，经历翻译后法尼基化，这是它们分配到膜所需的修饰。已经开发了特异性法尼基转移酶抑制剂（FTIs），其选择性地抑制这些蛋白质的加工。在细胞培养物和鼠模型中，FTI已被证明是肿瘤细胞生长的有效抑制剂，剂量对动物几乎没有毒性。这些数据表明，这些药物可能是有用的治疗剂。我们现在报道，当FTI与一些细胞毒性抗肿瘤药物联合使用时，对肿瘤细胞的作用是累加的。未发现干扰。此外，FTI和防止微管解聚的试剂，如紫杉醇或埃博霉素，协同作用以抑制细胞生长。FTI导致这些药物诱导中期阻滞的敏感性增加，表明法尼基化蛋白可能调节有丝分裂检查点。这些发现意味着FTI可能是一种有用的药物，用于治疗对紫杉烷类敏感的野生型ras肿瘤。
An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modification required for their partition to membranes. Specific farnesyl transferase inhibitors (FTIs) have been developed that selectively inhibit the processing of these proteins. FTIs have been shown to be potent inhibitors of tumor cell growth in cell culture and in murine models and at doses that cause little toxicity to the animal. These data suggest that these drugs might be useful therapeutic agents. We now report that, when FTI is combined with some cytotoxic antineoplastic drugs, the effects on tumor cells are additive. No interference is noted. Furthermore, FTI and agents that prevent microtubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth. FTI causes increased sensitivity to induction of metaphase block by these agents, suggesting that a farnesylated protein may regulate the mitotic check point. The findings imply that FTI may be a useful agent for the treatment of tumors with wild-type ras that are sensitive to taxanes.