Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034.
Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034.
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DOI：
10.1054/bjoc.2000.1601
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发表时间：
2001-02-02
影响因子：
8.8
通讯作者：
Cassidy J
中科院分区：
文献类型：
--
作者：
Bissett D;McLeod HL;Sheedy B;Collier M;Pithavala Y;Paradiso L;Pitsiladis M;Cassidy J
新型叶酸类似物AG2034被设计为GARFT(甘氨酰胺核糖核苷酸甲酰转移酶)的抑制剂，在英国癌症研究运动的赞助下进行了这一阶段的研究。AG2034通过抑制GARFT抑制从头合成嘌呤。共有28名经组织学证实为顽固性癌症的患者入选。AG2034短期静脉滴注，每3周1次。患者接受最多6个周期的8个剂量水平的评估，范围从1-11 mg/m2。剂量限制毒性表现为粘膜炎、腹泻和呕吐，剂量在6 mg/m2及以上。还记录到显著水平的血小板减少、中性粒细胞减少和贫血。其他零星的毒性包括疲劳和肌肉疼痛。AG2034的MTD为5 mg/m2。随着累积剂量的增加，大多数副作用发生的频率更高。与此相一致，药代动力学分析揭示了药物蓄积的证据。在所有接受检查的10名患者中，从第1周期到第3周期，AG2034AUC0-24的中位数增加了184%(范围为20%-389%)。在这项研究中没有观察到客观的抗肿瘤反应。©2001癌症研究活动http://www.bjcancer.com
The novel folate analogue AG2034, which was designed as an inhibitor of GARFT (glycinamide ribonucleotide formyltransferase), was evaluated in this phase I study under the auspices of The Cancer Research Campaign, UK. AG2034 blocks de novo purine synthesis through inhibition of GARFT. A total of 28 patients with histologically proven intractable cancers were enrolled. AG2034 was administered as a short intravenous infusion once every 3 weeks. 8 dose levels ranging from 1–11 mg/m2 were evaluated with patients receiving up to 6 cycles. Dose-limiting toxicities in the form of mucositis, diarrhoea and vomiting were observed at doses of 6 mg/m2 and above. Significant levels of thrombocytopenia, neutropenia and anaemia were also recorded. Other sporadic toxicities included fatigue and myalgia. The MTD with this schedule of AG2034 was 5 mg/m2. Most side effects occurred more frequently with cumulative dosing. In keeping with this, pharmacokinetic analysis revealed evidence of drug accumulation. The AG2034 AUC0–24 increased by a median of 184% (range 20–389%) from cycle 1 to 3 in all 10 patients examined. No objective antitumour responses were observed in the study. © 2001 Cancer Research Campaign http://www.bjcancer.com