Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine.
Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine.
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发表时间：
1999-10
期刊：
影响因子：
11.2
通讯作者：
Jiazhi Sun;M. Blaskovich;D. Knowles;Yimin Qian;J. Ohkanda;Ratna D. Bailey;Andrew D. Hamilton
中科院分区：
文献类型：
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作者：
Jiazhi Sun;M. Blaskovich;D. Knowles;Yimin Qian;J. Ohkanda;Ratna D. Bailey;Andrew D. Hamilton
Ras恶性转化需要法尼基转移酶（FTase）的翻译后修饰。在这里，我们报告的设计和抗肿瘤活性，在单药治疗以及与细胞毒性药物的联合治疗，一类新的非巯基含拟肽抑制剂的FTase和密切相关的家庭成员香叶基香叶基转移酶I（GGT酶I）。不含巯基的FTI-2148对FTase（IC 50，1.4 nM）的选择性高于GGT酶I（IC 50，1700 nM），而GGTI-2154对GGT酶I（21 nM）的选择性高于FTase（IC 50，5600 nM）。在全细胞中，相应的甲酯前药FTI-2153在抑制H-Ras（IC 50，10 nM）方面比Rap 1A加工强3000倍以上，而GGTI-2166在抑制Rap 1A（IC 50，300 nM）方面比H-Ras加工强100倍以上。此外，FTI-2153在抑制致癌H-Ras组成型丝裂原活化蛋白激酶活化和软琼脂中人肿瘤生长方面非常有效。FTI-2148以剂量依赖性方式抑制裸鼠中人肺腺癌A-549细胞的生长，抑制率分别为33%、67%和91%。FTI-2148与顺铂、吉西他滨或泰素的联合治疗比单药治疗产生更大的抗肿瘤疗效。在类似的抗肿瘤功效实验中，GGTI-2154的效力低于FTI-2148，并且抑制肿瘤生长9%、27%和46%。GGTI-2154与顺铂、吉西他滨或紫杉醇的联合治疗也更有效。最后，FTI-2148和GGTI-2154在全细胞中的选择性分别比我们先前报道的含巯基FTI-276和GGTI-297高30倍和33倍，效力分别高30倍和16倍。因此，我们的结果表明，这种高度有效和选择性的新型非含巯基的肽模拟物抑制整个动物中的人肿瘤生长，并且与细胞毒性剂的联合治疗比单一治疗更有益。
Ras malignant transformation requires posttranslational modification by farnesyltransferase (FTase). Here we report on the design and antitumor activity, in monotherapy as well as in combination therapy with cytotoxic agents, of a novel class of non-thiol-containing peptidomimetic inhibitors of FTase and the closely related family member geranylgeranyltransferase I (GGTase I). The non-thiol-containing FTI-2148 is highly selective for FTase (IC50, 1.4 nM) over GGTase I (IC50, 1700 nM), whereas GGTI-2154 is highly selective for GGTase I (21 nM) over FTase (IC50, 5600 nM). In whole cells, the corresponding methylester prodrug FTI-2153 is >3000-fold more potent at inhibiting H-Ras (IC50, 10 nM) than Rap1A processing, whereas GGTI-2166 is over 100-fold more selective at inhibiting Rap1A (IC50, 300 nM) over H-Ras processing. Furthermore, FTI-2153 was highly effective at suppressing oncogenic H-Ras constitutive activation of mitogen-activated protein kinase and human tumor growth in soft agar. FTI-2148 suppressed the growth of the human lung adenocarcinoma A-549 cells in nude mice by 33, 67, and 91% in a dose-dependent manner. Combination therapy of FTI-2148 with either cisplatin, gemcitabine, or Taxol resulted in a greater antitumor efficacy than monotherapy. GGTI-2154 in similar antitumor efficacy experiments is less potent than FTI-2148 and inhibits tumor growth by 9, 27, and 46%. Combination therapy of GGTI-2154 with cisplatin, gemcitabine, or Taxol is also more effective. Finally, FTI-2148 and GGTI-2154 are 30- and 33-fold more selective and 30- and 16-fold more potent in whole cells than our previously reported thiol-containing FTI-276 and GGTI-297, respectively. Thus, our results demonstrate that this highly potent and selective novel class of non-thiol-containing peptidomimetics inhibits human tumor growth in whole animals and that combination therapy with cytotoxic agents is more beneficial than monotherapy.