The ras signalling pathway as a target in cancer therapy.
The ras signalling pathway as a target in cancer therapy.
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ras 信号通路作为癌症治疗的靶点。
DOI：
10.1007/978-3-540-31209-3_8
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Olson,MichaelF
中科院分区：
文献类型：
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作者：
Graham,Kathryn;Olson,MichaelF
Ras GT3蛋白及其下游效应物调节参与许多生物过程的特定细胞内信号传导途径。它们的作用直接影响细胞周期的进展以及促凋亡因子和抗凋亡因子的微妙平衡。Ras控制的各种功能，以及新出现的证据表明Ras中的畸变以及下游信号通路中的多个点有助于肿瘤发生，表明Ras信号转导机制具有作为抗癌治疗靶点的显著潜力。许多基于靶向Ras信号通路的概念的新疗法处于临床前和临床开发的不同阶段。第一种“抗Ras”药物法尼基转移酶抑制剂（FTIs）的引入，被提出来中断Ras的关键翻译后修饰，导致人们对其潜在治疗益处的预期，但它们在临床试验中的总体表现未能达到这些高期望。这促使人们重新评估它们在癌症管理中的效用，并且它们作为Ras抑制剂的作用模式仍然存在激烈的争论。反义寡核苷酸疗法和小分子抑制剂的出现导致了针对Ras或特定通路组分的几种药剂的产生。这些药物在模型系统中的功效，以及对各种Ras效应物对癌症发病率和进展的贡献的不断增加的认识，鼓励了进一步开发新疗法。突出了药物开发的靶向蛋白质以及这些新型靶向疗法在临床试验中的有效性。还将探索通过替代手段抑制翻译后修饰的潜力。最后，我们将建议未来的目标和方向的癌症治疗，目标Ras功能。
The Ras GTPase proteins and their downstream effectors regulate specific intracellular signalling pathways involved in numerous biological processes. Their actions directly influence progression through the cell cycle and the delicate balance of pro-and anti-apoptotic factors. The variety of functions controlled by Ras, and the emerging evidence indicating that aberrations in Ras as well as at multiple points in downstream signalling pathways contribute to tumourigenesis, suggest that Ras signal transduction mechanisms have significant potential as anti-cancer therapeutic targets. A number of novel therapies based on the concept of targeting Ras signalling pathways are in various stages of pre-clinical and clinical development. The introduction of the first ‘anti-Ras’ agents, the farnesyl transferase inhibitors (FTIs), which were proposed to interrupt the crucial post-translational modification of Ras, led to much anticipation of their potential therapeutic benefits, but their overall performance in clinical trials has failed to live up to these high expectations. This has prompted a re-evaluation of their utility in cancer management, and where they have had some efficacy their mode of action as Ras inhibitors remains hotly debated. The advent of antisense oligonucleotide therapies and small-molecule inhibitors has resulted in the production of several agents directed against Ras or specific pathway components. The efficacy of these agents in model systems, as well as the increasing knowledge of the contribution made by various Ras effectors to the incidence and progression of cancer, has encouraged the development of further novel therapies.Here we will discuss the significance of Ras signal transduction in the neoplastic process, highlighting the proteins which have been targeted for drug development and the effectiveness of these novel targeted therapies in clinical trials. The potential of inhibiting post-translational modification by alternative means will also be explored. Finally we will suggest future aims and directions for cancer therapies that target Ras function.