Krug L M, Ng K K, Kris M G, Miller V A, Tong W, Heelan R T, Leon L, Leung D, Kelly J, Grant S C, Sirotnak F M
Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York 10021, USA.
Clin Cancer Res. 2000 Sep;6(9):3493-8.
The 10-deazaaminopterins are a new class of rationally designed antifolates demonstrating greater antitumor effects than methotrexate in murine tumor models and human tumor xenografts. Their design was aimed at improving membrane transport and polyglutamylation in tumor cells, resulting in increased intracellular accumulation and enhanced cytotoxicity. Compared with other 4-aminofolate analogues, 10-propargyl-10-deazaaminopterin (PDX) is the most efficient permeant for the RFC-1-mediated internalization and substrate for folylpolyglutamate synthetase. PDX demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate or edatrexate. We undertook a Phase I study with PDX to identify the potential toxicities and define an optimal dose and schedule. Thirty-three patients were enrolled, all of whom had non-small cell lung cancer (NSCLC) and were treated previously with a median of two prior chemotherapy regimens. Initially, PDX was administered weekly for 3 weeks in a 4-week cycle. Mucositis requiring dose reduction and/or delay in the first cycle occurred in four of six patients treated at the initial dose level (30 mg/m2), making this the maximal tolerated dose for PDX given on this schedule. The treatment schedule was then modified to every 2 weeks. Twenty-seven patients were treated twice weekly with a total of 102 four-week cycles (median, 2 cycles/patient). Mucositis was the dose-limiting toxicity, with grade 3 and 4 mucositis occurring in the first two patients treated at the 170 mg/m2 dose level. Other toxicities were mild and reversible. No neutropenia was observed. The recommended Phase II dose is 150 mg/m2 biweekly. At that dose level, the mean area under the curve was 20.6 micromol x h, and the mean terminal half-life was 8 h. Two patients with stage IV NSCLC had major objective responses, and five patients had stable disease for 7 (two patients), 9 (one patient), 10 (one patient), and 13 months (one patient). PDX is a new antifolate with manageable toxicity and evidence of antitumor activity in NSCLC. A Phase II trial in NSCLC and a Phase I trial with paclitaxel are under way. These studies will also quantitate the expression of genes controlling internalization (RFC-1) and polyglutamylation of PDX in tumor cells as correlates of response.
10-脱氮氨基蝶呤是一类新的经合理设计的抗叶酸剂，在小鼠肿瘤模型和人肿瘤异种移植模型中显示出比甲氨蝶呤更强的抗肿瘤作用。其设计目的是改善肿瘤细胞中的膜转运和多聚谷氨酸化，从而增加细胞内蓄积并增强细胞毒性。与其他4-氨基叶酸类似物相比，10-炔丙基-10-脱氮氨基蝶呤（PDX）是通过还原叶酸载体-1（RFC-1）介导的内化作用最有效的通透剂，也是叶酸多聚谷氨酸合成酶的底物。PDX在体外和体内均显示出比甲氨蝶呤或依达曲沙更强的抗肿瘤疗效。我们开展了一项关于PDX的I期研究，以确定其潜在毒性并确定最佳剂量和给药方案。入组了33例患者，所有患者均患有非小细胞肺癌（NSCLC），之前接受过的化疗方案中位数为两种。最初，PDX以4周为一个周期，每周给药1次，共3周。在初始剂量水平（30mg/m²）接受治疗的6例患者中有4例在第一个周期出现了需要降低剂量和/或延迟给药的黏膜炎，这使得该给药方案下PDX的最大耐受剂量为此剂量。随后将治疗方案改为每2周给药1次。27例患者每周给药2次，共进行了102个4周周期（中位数为每位患者2个周期）。黏膜炎是剂量限制性毒性反应，在以170mg/m²剂量水平治疗的前2例患者中出现了3级和4级黏膜炎。其他毒性反应较轻且可逆转。未观察到中性粒细胞减少。推荐的II期剂量为每2周150mg/m²。在该剂量水平下，曲线下平均面积为20.6微摩尔·小时，平均终末半衰期为8小时。2例IV期NSCLC患者出现了主要客观缓解，5例患者病情稳定达7个月（2例患者）、9个月（1例患者）、10个月（1例患者）和13个月（1例患者）。PDX是一种新的抗叶酸剂，毒性可控，在NSCLC中具有抗肿瘤活性证据。一项NSCLC的II期试验和一项与紫杉醇联合的I期试验正在进行中。这些研究还将定量肿瘤细胞中控制PDX内化（RFC-1）和多聚谷氨酸化的基因表达，作为反应的相关指标。
