Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.
Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.
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发表时间：
2003-02
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通讯作者：
A. Lockhart;R. Braun;Daohai Yu;Joel R. Ross;M. Dewhirst;J. Humphrey;S. Thompson;K. Williams
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作者：
A. Lockhart;R. Braun;Daohai Yu;Joel R. Ross;M. Dewhirst;J. Humphrey;S. Thompson;K. Williams
目的评价一种新的创面血管生成实验方法应用于广谱基质金属蛋白酶抑制剂BMS-275291的I期研究的可行性，并确定创面血管生成实验是否能够检测到BMS-275291对血管生成的抑制作用。实验设计在治疗开始前，进行4 mm皮肤活检。对伤口进行了14天的成像。治疗在第0天开始，14天后进行单独的4毫米活组织检查。第二个伤口也进行了14天的成像。伤口血管生成由两名独立的观察者评分，他们对治疗状态视而不见。结果观察者1治疗前达到1.5和2.0目标平均血管评分的中位天数(95%可信区间)分别为3.7(2.2~6.9)和8.0(5.0~10.0)，治疗后分别为4.9(3.7~8.0)和9.3(7.0~11.5)。达到1.5个AVS的中位时间延迟1.2天，与治疗前相比减少了32%(P=0.06)。对于目标AVS为2.0的患者，治疗前和治疗中的中位时间延迟为1.3天或减少16%(P=0.04)。结论本研究建立的创面血管生成实验方法实用、耐受性好、重复性好。用这项检测可以检测到由于bms-275291导致的伤口血管生成的延迟。这项技术值得在其他抗血管生成药物的临床试验中进行进一步的研究。
PURPOSE The purpose of this study was to evaluate the feasibility of incorporating a novel wound angiogenesis assay into a Phase I study of BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor, and to determine whether the wound angiogenesis assay was able to detect the inhibition of angiogenesis in patients treated with BMS-275291. EXPERIMENTAL DESIGN Before treatment began, a 4-mm skin biopsy was performed. The wound was imaged for 14 days. Treatment was started on day 0, and a separate 4-mm biopsy was performed 14 days later. The second wound was also imaged for 14 days. Wound angiogenesis was scored by two independent observers who were blinded to treatment status. RESULTS The median times in days (95% confidence interval) to reach the target average vascular score (AVS) of 1.5 and 2.0 based on the data of Observer 1 were 3.7 (2.2-6.9) and 8.0 (5.0-10.0) pretreatment whereas on-treatment the values were 4.9 (3.7-8.0) and 9.3 (7.0-11.5), respectively. The delay in the median time to reach an AVS of 1.5 was 1.2 days or a 32% reduction when comparing pretreatment with on-treatment (P = 0.06). For the target AVS of 2.0 the delay in the median time pretreatment versus on-treatment was 1.3 days or a 16% reduction (P = 0.04). CONCLUSIONS The wound angiogenesis assay used in this study was practical, well tolerated, and reproducible. Delays in wound angiogenesis because of BMS-275291 were detectable with this assay. This technique warrants additional investigation in clinical trials of other antiangiogenic agents.