Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors
Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors
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DOI：
10.1093/annonc/mdm140
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发表时间：
2007-08-01
影响因子：
50.5
通讯作者：
Eckhardt, S. G.
中科院分区：
文献类型：
--
作者：
Hariharan, S.;Gustafson, D.;Eckhardt, S. G.
背景：西伦吉肽是一种抑制整合素α (nu) β(3)和α (nu) β(5)与细胞外基质结合的抗血管生成药物，在癌症患者中研究了两种剂量水平，以确定最佳生物剂量。患者和方法：给药剂量分别为600或1200mg /m(2)，每周2次，每次1 -h，每28d。采用了一种基于生物活性率的新型剂量递增方案。结果：20例患者接受了50个疗程的纤毛霉素治疗，无剂量限制性毒性反应。药代动力学（PK）分析显示，消除半衰期短，为4小时，支持每周两次给药。在评估的6种可溶性血管生成分子中，只有e -选择素较基线显著增加。由于患者肿瘤的异质性，肿瘤微血管密度和基因表达的分析不能提供信息。虽然一些可评估的肿瘤活检对患者确实显示治疗后肿瘤和覆盖细胞凋亡增加，但由于上述异质性，这些结果没有达到统计学意义。结论：西伦吉肽是一种耐受性良好的抗血管生成药物。本研究中选择的生物标志物强调了在缺乏有效的生物分析的情况下评估抗血管生成药物生物活性的困难。
Background: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose.Patients and methods: The doses of cilengiticle were 600 or 1200 mg/m(2) as a 1 -h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate.Results: Twenty patients received 50 courses of cilengiticle with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and enclothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity.Conclusions: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.