'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group.
'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group.
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“Tomudex”（ZD1694）：一种新型胸苷酸合成酶抑制剂，在一系列实体瘤中具有临床抗肿瘤活性。
DOI：
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发表时间：
1996
影响因子：
50.5
通讯作者：
Leonard W. Seymour
中科院分区：
文献类型：
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作者：
David Cunningham;John Zalcberg;Ian E. Smith;M. Gore;R. Pazdur;H. Burris;Neal J Meropol;G. Kennealey;Leonard W. Seymour
背景
甲氨蝶呤（MTX）和5-氟尿嘧啶（5-FU）等抗代谢药物已在临床上使用多年。虽然它们的作用部分是由于胸苷酸合成酶（TS）抑制，但它们也对RNA和嘌呤合成具有非特异性、非TS作用。因此，直接和特异的TS抑制剂提出了一个有吸引力的研究目标。癌症研究所和Zeneca制药公司之间的合作研究导致了基于叶酸的喹唑啉TS抑制剂的设计。ZD 1694（“Tomudex”）是这些药物中第一个达到高级临床开发的药物，目前正在完成III期研究。
设计
使用“Tomudex”（3.0 mg/m2）进行了8项II期试验，以15分钟短时间输注给药，每周3次。
结果
“Tomudex”在一系列肿瘤类型中表现出活性，最显著的是晚期结直肠癌和乳腺癌（客观反应率26%），并且具有可接受的毒性：最常见的WHO 3级和4级不良事件是肝转氨酶的自限性可逆增加、短暂性白细胞减少、腹泻、恶心和呕吐以及疲劳或不适。粘膜炎/口腔炎、脱发和皮肤毒性的发生率较低且强度较轻。
结论
“Tomudex”代表了合理药物设计计划的成功高潮，并显示出作为治疗结直肠癌的新细胞毒性药物的前景。计划在其他肿瘤类型中进行进一步研究。
BACKGROUND
Anti-metabolites such as methotrexate (MTX) and 5-fluorouracil (5-FU) have been used clinically for many years. Although their effects are partly due to thymidylate synthase (TS) inhibition, they also have non-specific, non TS effects on RNA and purine synthesis. Direct and specific TS inhibitors therefore presented an attractive research target. Collaborative research between the Institute of Cancer Research and Zeneca Pharmaceuticals led to the design of specific folate based quinazoline TS inhibitors. ZD1694 ('Tomudex'), the first of these drugs reaching advanced clinical development, is currently completing phase III studies.
DESIGN
Eight phase II trials were carried out using 'Tomudex', 3.0 mg/m2, given as a short 15-minute infusion 3-weekly.
RESULTS
'Tomudex' demonstrates activity in a range of tumour types, most notably advanced colorectal and breast cancer (objective response rate 26%) and has acceptable toxicity: the most common WHO grade 3 and 4 adverse events were self-limiting reversible increases in liver transaminases, transient leucopenia, diarrhoea, nausea and vomiting and tiredness or malaise. Mucositis/stomatitis, alopecia and skin toxicity were notable for their low incidence and mild intensity.
CONCLUSIONS
'Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer. Further studies in other tumour types are planned.