de Jonge M J A, Verweij J
Dept. Of Medical Oncology, Erasmus University Medical Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
Eur J Cancer. 2006 Jul;42(10):1351-6. doi: 10.1016/j.ejca.2006.02.013. Epub 2006 Jun 5.
Recent insight into the role of receptor tyrosine kinase function in cancer cells culminated in the design of highly selective tyrosine kinase inhibitors. After proof of concept for the clinical efficacy and tolerability of selective tyrosine kinase inhibitors, it was conceived that most tumours will depend on more than one signalling pathway for their growth and survival. As a consequence, different strategies were pursued to inhibit multiple signalling pathways or multiple steps in the same pathway either by the development of multi-targeted agents or the combination of single targeted drugs. The use of a combination of different compounds will be less convenient to the patient, may result in dosing mistakes and drug-drug interaction should be anticipated. However, this approach will enable the titration of the dose of either agent to optimize target inhibition. The use of multi-targeted agents will circumvent several of the problems of combination therapy. Clinical activity resulting in FDA approval for both BAY 43-9006 and SU11248 has been noted. However, optimal inhibition of several targets might not be feasible at a dose with acceptable toxicity.
近期对受体酪氨酸激酶功能在癌细胞中作用的深入了解，最终促成了高选择性酪氨酸激酶抑制剂的设计。在证实了选择性酪氨酸激酶抑制剂的临床疗效和耐受性后，人们认识到大多数肿瘤的生长和存活依赖于不止一条信号通路。因此，人们采取了不同策略，通过开发多靶点药物或联合单一靶点药物来抑制多条信号通路或同一通路中的多个步骤。使用不同化合物的组合对患者来说不太方便，可能会导致用药错误，并且应预期会出现药物相互作用。然而，这种方法能够调整任一药物的剂量以优化靶点抑制。使用多靶点药物将规避联合治疗的几个问题。已注意到BAY 43 - 9006和SU11248均获得FDA批准的临床活性。然而，在具有可接受毒性的剂量下，对多个靶点的最佳抑制可能不可行。
