Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.
Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.
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DOI：
10.1038/sj.bjc.6600992
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发表时间：
2003-06-16
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
5，6-二甲基咕吨酮-4-乙酸（DMXAA）的抗肿瘤作用是通过肿瘤选择性抗血管效应和细胞因子诱导介导的。本临床I期试验旨在检查其毒性、最大耐受剂量、药代动力学（PK）和药效学（PD）。次要目的是评估其抗肿瘤疗效。DMXAA每3周一次，静脉输注20分钟。剂量递增最初遵循改良的斐波那契方案，但也受PK和毒性的指导。共有63名患者接受了161个疗程的DMXAA，剂量范围为6至4900 mg m−2。DMXAA在较低剂量下耐受良好，未观察到药物相关的骨髓抑制。在4900 mg m−2剂量下观察到快速可逆的剂量限制性毒性，包括意识模糊、震颤、言语不清、视觉障碍、焦虑、尿失禁和可能的左心室衰竭。在接受2000 mg m−2及以上剂量评价的13例患者中观察到校正的心脏QT间期一过性延长。1例转移性宫颈癌患者在1100 mg m−2剂量下获得未经证实的部分缓解，8个疗程后进展。单独报告PK和PD研究的结果。DMXAA在耐受良好的剂量下具有抗肿瘤活性。
The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m−2. DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m−2, including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m−2 and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m−2, progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.
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DOI：
10.1016/0277-5379(89)90072-2
发表时间：
1989-09-01
期刊：
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY
影响因子：
--
作者：
KERR, DJ;KAYE, SB
通讯作者：
KAYE, SB
影响因子：
2.9
作者：
Brown, TM;Skop, BP;Mareth, TR
通讯作者：
Mareth, TR
影响因子：
8.8
作者：
Griggs J;Hesketh R;Smith GA;Brindle KM;Metcalfe JC;Thomas GA;Williams ED
通讯作者：
Williams ED
DOI：
10.1016/0360-3016(94)90292-5
发表时间：
1994-05-15
影响因子：
7
作者：
CLIFFE, S;TAYLOR, ML;WILSON, WR
通讯作者：
WILSON, WR
影响因子：
4.7
作者：
Eggermont, A M;ten Hagen, T L
通讯作者：
ten Hagen, T L