The use of molecular markers in farnesyltransferase inhibitor (FTI) therapy of breast cancer
The use of molecular markers in farnesyltransferase inhibitor (FTI) therapy of breast cancer
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DOI：
10.1023/a:1015209123900
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发表时间：
2002-05-01
影响因子：
3.8
通讯作者：
Rosen, N
中科院分区：
文献类型：
--
作者：
Moasser, MM;Rosen, N
Ras的药理学抑制剂可以是有效的抗癌剂的假设已经导致法尼基转移酶抑制剂（FTI）的发展。这些试剂抑制包括Ras在内的许多细胞蛋白质的必要加工。FTI在临床前模型中显示出良好的抗肿瘤疗效和较小的毒性，基于这些结果，目前正在进行许多临床试验，以评估这些药物在癌症患者中的临床潜力。然而，与导致其设计的想法相反，机理研究尚未证实它们通过抑制Ras抑制肿瘤。FTI在体外抑制多种人类肿瘤细胞的生长，迄今为止的研究尚未确定预测这类药物抗肿瘤疗效的细胞特征。我们研究了一组乳腺癌细胞系，它们对FTI的敏感性差异很大，以确定哪些分子特征可能决定对这类药物的敏感性。在这些细胞中，我们发现FTI敏感性与Ras亚型的相对表达或Ras加工、生长因子信号传导、雌激素受体表达或生长因子受体过表达的抑制无关。寻找FTI敏感性的其他分子相关性，我们比较了这些细胞中法尼基蛋白转移酶（FPT酶）的活性，虽然我们没有发现与FTI敏感性的总体相关性，但我们发现两种具有异常低的FPT酶活性的细胞系是敏感的。比较p53基因型与FTI敏感性，我们发现，虽然我们的面板中的大多数细胞系具有突变型p53，所有三个细胞系与野生型p53是相当敏感的FTI。事实上，具有野生型p53和最低FPTase活性的MCF-7细胞是我们所见过的对FTI最敏感的细胞类型。虽然这些研究没有确定任何单一的分子标志物，可以准确地预测FTI敏感性在乳腺肿瘤，他们强调了FPTase活性和p53功能的潜在作用，以进一步分析。
The hypothesis that pharmacologic inhibitors of Ras can be effective anti-cancer agents has led to the development of Farnesyltransferase inhibitors (FTIs). These agents inhibit the requisite processing of a number of cellular proteins including Ras. FTIs have shown good anti-tumor efficacy and little toxicity in preclinical models and based on these results, numerous clinical trials are currently underway to evaluate the clinical potential of these agents in patients with cancer. However, contrary to the ideas that led to their design, mechanistic studies have not confirmed that they inhibit tumors through the inhibition of Ras. FTIs inhibit the growth of a broad variety of human tumor cells in vitro and studies to date have not identified cellular characteristics that predict the anti-tumor efficacy of this class of agents. We have studied a panel of breast cancer cell lines that differ widely in their sensitivity to FTI in order to determine which molecular characteristics may determine sensitivity to this class of agents. In these cells we find that FTI sensitivity does not correlate with the relative expression of Ras isoforms or the inhibition of Ras processing, growth factor signaling, expression of estrogen receptor or the overexpression of growth factor receptors. Looking for other molecular correlates of FTI sensitivity we have compared the activity of farnesylprotein transferase (FPTase) among these cells and although we find no overall correlation with FTI sensitivity, we find that two cell lines with unusually low FPTase activity are sensitive. Comparing p53 genotype with FTI-sensitivity we find that although most cell lines in our panel have mutant p53, all three cell lines with wild-type p53 are quite sensitive to FTI. In fact, MCF-7 cells which have both wild-type p53 and the lowest FPTase activity are the most FTI-sensitive cell type we have ever seen. Although these studies do not identify any single molecular marker that can accurately predict FTI sensitivity in breast tumors, they highlight the potential roles of FPTase activity and p53 function for further analysis.