Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland.
Curr Drug Targets. 2010 Jan;11(1):37-47. doi: 10.2174/138945010790030974.
Pemetrexed is a newer antifolate drug that has been approved as first-line treatment for patients with advanced non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory NSCLC after platinum-containing chemotherapy, at a dose of 500 mg/m(2). Pemetrexed undergoes intracellular activation by poly-gamma-glutamylation, that is essential for its antiproliferative activity. Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism, i.e. thymidylates synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with TYMS being the most relevant target. Pemetrexed undergoes rapid renal elimination as unchanged parent compound, with a terminal half-life of between two to five hours. In later clinical development, the usefulness of supplementation with folic acid and vitamin B(12) became evident, to control pemetrexed-related toxicity. The results from the phase III upfront registration study, a retrospective observational data, and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed, Pemetrexed is active in patients with non-squamous cell NSCLC while no benefit is seen in patients with squamous-cell histology, possibly as a result of different expression of intratumoral TYMS. These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC.
培美曲塞是一种新型叶酸拮抗剂药物，已被批准用于与顺铂联合治疗晚期非鳞状非小细胞肺癌（NSCLC）的一线治疗，以及在含铂化疗后复发或化疗耐药的 NSCLC 的单药治疗，剂量为 500mg/m2。培美曲塞通过聚γ-谷氨酸化进行细胞内激活，这对于其抗增殖活性是必不可少的。聚谷氨酸衍生物主要抑制细胞内叶酸代谢的三个关键酶，即胸苷酸合酶（TYMS）、二氢叶酸还原酶（DHFR）和甘氨酰胺核苷酸甲酰转移酶（GARFT），其中 TYMS 是最相关的靶标。培美曲塞主要以未改变的母体化合物形式经肾脏快速消除，终末半衰期为两到五小时。在后期的临床开发中，补充叶酸和维生素 B12 的有效性变得明显，以控制培美曲塞相关的毒性。来自 III 期一线注册研究、回顾性观察数据和最近的 NSCLC 培美曲塞维持治疗研究的结果表明，组织学亚型是接受培美曲塞治疗的患者临床结局的最重要预测标志物，培美曲塞在非鳞状细胞 NSCLC 患者中有效，而在鳞状细胞组织学患者中无效，可能是由于肿瘤内 TYMS 的表达不同。这些是为晚期 NSCLC 患者个体化抗癌治疗迈出的重要步骤。
