Overview of phase I trials of multitargeted antifolate (MTA, LY231514).
Overview of phase I trials of multitargeted antifolate (MTA, LY231514).
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多靶点抗叶酸药物 I 期试验概述（MTA，LY231514）。
作者：
D. Rinaldi
多靶向抗叶酸（MTA, LY231514）是一种新型的抗叶酸抗代谢药物，通过抑制胸苷酸合成酶、甘氨酸酰胺甲酰基转移酶和二氢叶酸还原酶具有抗肿瘤活性。在I期设置中研究了三种给药方案：每日x5每21天，每周x4每42天，每21天一次。这些方案的最大耐受剂量分别为4.0 mg/m2、30 mg/m2和600 mg/m2。在所有方案中观察到的主要剂量限制性毒性是中性粒细胞减少，在每日x5方案中观察到更大程度的可逆性肝脏生化紊乱。考虑到毒性是可控的和可逆的，抗肿瘤活性表现出来，以及每21天给药计划的便利性，该计划被选择用于II期评估。
Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.