Kohl N E
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Ann N Y Acad Sci. 1999;886:91-102. doi: 10.1111/j.1749-6632.1999.tb09404.x.
The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is currently being tested in the clinic.
Ras蛋白是低分子量的GTP结合蛋白，在调节从细胞膜到细胞核的生长增殖信号转导中发挥作用。在所有人类癌症中，约25%存在致癌性突变的ras基因。Ras癌蛋白定位于质膜内表面对其生物学活性至关重要。这一观察结果表明，介导膜定位的酶——法尼基蛋白转移酶（FPTase）将成为新型抗癌药物开发的靶点。我们已经开发出强效的、具有细胞活性的FPTase抑制剂，这些抑制剂在细胞培养中表现出抗增殖活性，并能阻断与Ras诱导的单层培养哺乳动物细胞转化相关的形态学改变。在体内，这些化合物在裸鼠异种移植模型中可阻断ras转化的成纤维细胞的生长，并在几种ras转基因小鼠品系中阻断乳腺和唾液腺肿瘤的生长，在某些情况下还可使其消退，且未发现任何可检测到的副作用。我们的临床前研究结果以及其他研究结果表明，法尼基转移酶抑制剂（FTIs）可能对多种人类癌症有效，这一假设目前正在临床中进行验证。
