Farnesyltransferase inhibitors: targeting the molecular basis of cancer.
Farnesyltransferase inhibitors: targeting the molecular basis of cancer.
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法呢基转移酶抑制剂：针对癌症的分子基础。
DOI：
10.1016/s0304-419x(99)00007-4
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Allen Oliff
中科院分区：
文献类型：
--
作者：
Allen Oliff
尽管在过去20年中在癌症研究方面投入了大量的智力和财力资源，但恶性肿瘤仍然是发达国家的第二大死亡原因。虽然改进的手术和放射治疗技术可以治愈大多数存在局限性肿瘤的患者，但只有10^ 12%的播散性癌症患者可以通过现有的化疗治愈[1]。显然，需要更有效的治疗。鉴定更有效的治疗方法的一种方法是将药物发现工作集中在负责哺乳动物细胞转化的基本分子机制上。鉴于近年来我们对癌症的生物化学、细胞生物学和遗传基础的理解急剧扩展，这种方法特别有吸引力。我们现在知道，三种类型的遗传改变或突变构成了几乎所有癌症的发病机制。这些突变出现在癌基因、肿瘤抑制基因和控制DNA忠实复制的基因中，例如DNA修复酶和细胞检查点基因。不幸的是，大多数引起癌症的突变出现在肿瘤抑制基因和DNA修复酶中，导致编码蛋白质的功能丧失。遭受功能丧失突变的蛋白质对于药物疗法的创建是不良的靶点，因为小的有机分子很少能够将生物活性构象恢复到被扭曲或变性的突变蛋白质。相比之下，癌基因的突变通常会导致其编码蛋白质的功能改变。携带功能突变的癌基因是药物干预的更具吸引力的靶点，因为使用传统的药物筛选策略更容易识别出阻断酶或特异性受体配体增强活性的小有机分子[2]。
Despite the investment of substantial intellectual and ónancial resources in cancer research over the past 20 years, malignancies remain the second leading cause of death in the developed world. While improved surgical and radiotherapy techniques permit the cure of most patients who present localized tumors, only 10^ 12% of the patients with disseminated cancer are cured by existing chemotherapies [1]. Clearly, more effective treatments are needed. One approach to the identiócation of more effective therapeutics is to focus drug discovery efforts on the fundamental molecular mechanisms responsible for mammalian cell transformation. This approach is particularly attractive in the light of the dramatic expansion of our understanding of the biochemical, cell biological and genetic basis of cancer that has accrued in recent years. We now know that three types of genetic alterations or mutations underlie the pathogenesis of virtually all cancers. These mutations arise in oncogenes, tumor suppressor genes and genes that govern the faithful replication of DNA, eg DNA repair enzymes and cellular checkpoint genes. Unfortunately, most of the cancer causing mutations that arise in tumor suppressor genes and DNA repair enzymes result inloss of function'changes for the encoded proteins. Proteins sufferingloss of function'mutations make poor targets for the creation of drug therapies since small organic molecules are rarely capable of restoring the biologically active conformation to mutated proteins that are distorted or denatured. By contrast, mutations arising in oncogenes generally result ingain of function'changes for their encoded proteins. Oncogenes harboringgain of function'mutations are far more attractive targets for pharmaceutical intervention, because small organic molecules that block the enhanced activities of enzymes or ligands for specióc receptors are much more readily identióed using traditional drug screening strategies [2].
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DOI：
10.1073/pnas.95.4.1369
发表时间：
1998-02
影响因子：
11.1
作者：
M. Moasser;L. Sepp-Lorenzino;N. Kohl;A. Oliff;A. Balog;D. Su;S. Danishefsky;N. Rosen
通讯作者：
M. Moasser;L. Sepp-Lorenzino;N. Kohl;A. Oliff;A. Balog;D. Su;S. Danishefsky;N. Rosen
法尼基转移酶抑制剂 FTI-277 可使 H-ras 转化的大鼠胚胎成纤维细胞放射增敏。
DOI：
--
发表时间：
1996
期刊：
Cancer research.
影响因子：
--
作者：
Bernhard,EJ;Kao,G;Cox,AD;Sebti,SM;Hamilton,AD;Muschel,RJ;McKenna,WG
通讯作者：
McKenna,WG
影响因子：
11.2
作者：
Ramón Mangues;Teresa Corral;N. Kohl;W. Symmans;Suying Lu;Marcos Malumbres;J. Gibbs;A. Oliff;A. Pellicer
通讯作者：
Ramón Mangues;Teresa Corral;N. Kohl;W. Symmans;Suying Lu;Marcos Malumbres;J. Gibbs;A. Oliff;A. Pellicer
法呢基转移酶抑制剂诱导拒绝与基质附着的 Ras 转化细胞的凋亡。
DOI：
--
发表时间：
1997
期刊：
Cancer research.
影响因子：
--
作者：
Lebowitz,PF;Sakamuro,D;Prendergast,GC
通讯作者：
Prendergast,GC
影响因子：
11.2
作者：
L. Sepp-Lorenzino;Zhenping Ma;E. Rands;N. Kohl;J. Gibbs;A. Oliff;N. Rosen
通讯作者：
L. Sepp-Lorenzino;Zhenping Ma;E. Rands;N. Kohl;J. Gibbs;A. Oliff;N. Rosen