University of California Davis Cancer Center, Sacramento, 95817, USA.
Curr Drug Targets. 2010 Jan;11(1):85-94. doi: 10.2174/138945010790030983.
Both the multi-targeted antifolate pemetrexed and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib have established roles in the treatment of advanced non-small cell lung cancer (NSCLC). Given different mechanisms of action and minimal overlapping toxicities, combinations of these agents have been considered. However, four previous phase III trials investigating concurrent chemotherapy with or without EGFR TKIs showed no clinical benefit. Based on preclinical data, we developed a model of pharmacodynamic separation to avoid potential negative interactions between chemotherapy and EGFR TKIs in tumors containing wild-type EGFR. This review summarizes the background, scientific rationale and early clinical data in support of intercalation of intermittent erlotinib dosing with pemetrexed as a means of achieving pharmacodynamic separation. Ongoing research efforts investigating this concept are reviewed.
多靶点抗叶酸药物培美曲塞和表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）厄洛替尼在治疗晚期非小细胞肺癌（NSCLC）方面均有明确的作用。鉴于这些药物具有不同的作用机制和最小的重叠毒性，因此考虑将这些药物联合应用。然而，之前进行的四项评估联合化疗加或不加 EGFR TKI 的 III 期临床试验并未显示出临床获益。基于临床前数据，我们开发了一种药效分离模型，以避免在含有野生型 EGFR 的肿瘤中化疗和 EGFR TKI 之间可能存在的负相互作用。本文综述了支持培美曲塞联合间歇性厄洛替尼给药以实现药效分离的背景、科学原理和早期临床数据。还综述了正在进行的研究工作。
