Haluska P, Dy G K, Adjei A A
Department of Internal Medicine, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Eur J Cancer. 2002 Sep;38(13):1685-700. doi: 10.1016/s0959-8049(02)00166-1.
Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.
由法尼基蛋白转移酶催化的蛋白质法尼基化涉及将一个15碳的法尼基基团添加到某些蛋白质羧基末端的保守氨基酸残基上。法尼基转移酶的蛋白质底物包括几种G蛋白，它们是细胞信号传导和细胞骨架组织的关键中间体，如Ras、Rho、PxF以及核纤层蛋白A和B。活化的Ras蛋白通过PI3激酶/AKT途径的顺序激活引发一系列磷酸化事件，PI3激酶/AKT途径对细胞存活至关重要，而Raf/Mek/Erk激酶途径与细胞增殖有关。在30%的人类癌症中发现了编码组成型活化蛋白的Ras突变。由于Ras的法尼基化是其转化和增殖活性所必需的，因此法尼基蛋白转移酶抑制剂被设计为抗癌药物以消除Ras功能。然而，目前的证据表明，法尼基转移酶抑制剂的抗癌活性可能不仅仅是由于抑制Ras。本综述将讨论目前正在进行临床试验的其中三种药物的现有临床数据。
