Sartore-Bianchi A, Ricotta R, Cerea G, Maugeri M R, Siena S
The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy.
Int J Biol Markers. 2007 Jan-Mar;22(1 Suppl 4):S77-87.
During the last 10 years, the concept of targeted biological therapy for the treatment of cancer has emerged. Targeted agents entered clinical practice only recently, and the first drugs with demonstrated clinical efficacy were mainly inhibitors of the ErbB family of receptors (i.e., EGFR and HER-2), either monoclonal antibodies (MAbs) or tyrosine kinase inhibitors (TKIs). After the proof of concept for the clinical efficacy and tolerability of these selective agents, it was conceived that most tumors will depend on more than one signaling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signaling pathways or multiple steps in the same pathway, either by the development of multi-targeted agents or the combination of single targeted drugs. The recent FDA and EMEA approval of sorafenib and sunitinib, both multi-targeted TKIs, marked the coming of age of this new generation of drugs. Now a whole new wave of multi-targeted compounds is moving into clinical trials, raising in the minds of investigators important questions about the best strategies to pursue in their use and many doubts about their differences and the seeming redundancies in the pipelines of pharmaceutical companies. This review will deal with the rationale underlying the multi-targeted approach and with the available clinical experience with multi-targeted agents, especially focusing on molecules with anti- EGFR mechanisms of action.
在过去10年中，出现了用于治疗癌症的靶向生物疗法的概念。靶向药物直到最近才进入临床实践，首批具有临床疗效的药物主要是ErbB受体家族（即EGFR和HER-2）的抑制剂，包括单克隆抗体（MAbs）或酪氨酸激酶抑制剂（TKIs）。在证实了这些选择性药物的临床疗效和耐受性之后，人们设想大多数肿瘤的生长和存活将依赖于不止一种信号通路。因此，人们采取了不同策略来抑制多种信号通路或同一通路中的多个步骤，要么通过开发多靶点药物，要么通过联合使用单一靶向药物。美国食品药品监督管理局（FDA）和欧洲药品管理局（EMEA）最近批准了索拉非尼和舒尼替尼这两种多靶点TKIs，标志着这新一代药物的成熟。现在，全新一波的多靶点化合物正在进入临床试验，这在研究人员心中引发了关于使用这些药物的最佳策略的重要问题，以及对它们之间的差异和制药公司产品线中看似冗余之处的诸多疑问。本综述将探讨多靶点方法的基本原理以及多靶点药物的现有临床经验，尤其关注具有抗EGFR作用机制的分子。
