Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors
Phase I clinical trial of oral 2-methoxyestradiol, an antiangiogenic and apoptotic agent, in patients with solid tumors
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DOI：
10.4161/cbt.5.1.2349
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Figg, WD
中科院分区：
文献类型：
--
作者：
Dahut, WL;Lakhani, NJ;Figg, WD
目的：确定口服新型抗癌药物 2-甲氧基雌二醇 (2ME2) 在实体瘤患者中的最大耐受剂量 (MTD) 和毒性特征。材料和方法：纳入了 20 名难治性实体瘤患者。 2ME2 以 400 mg bid 开始口服，剂量逐渐增加直至 3000 mg bid。在开始用药之前和之后进行肿瘤活检，以通过 CD 31 评估微血管密度，并通过 Ki67 免疫组织化学评估细胞增殖。在首次单次口服给药后 50 小时内收集系列血浆样本，用于表征药代动力学，并使用液相色谱串联质谱法进行分析。 结果：11 名男性和 9 名女性接受 2ME2，剂量水平为 400 mg bid (n=3)、800 mg bid (n=3)、1600 mg bid (n=6)、2200 mg bid (n=5) 和 3000 mg bid (n=3)。没有剂量限制性毒性，因此未定义 MTD。 2ME2 治疗第 38 天，1600 mg bid 剂量水平出现 1 次 4 级血管性水肿发作。其他毒性为轻度至中度。一名卵巢透明细胞癌患者在 1600 mg bid 剂量水平下出现部分缓解，持续三年以上。结论：在 3000 mg bid 剂量下未达到 2ME2 的 MTD。该试验因 2ME2 血浆浓度相对于给药剂量极低而结束。 2ME2 处理对微血管密度（CD31 免疫染色）和细胞增殖（Ki-67 免疫染色）没有影响。目前正在开发一种具有更高生物利用度的 2ME2 新配方。
Purpose: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors.Materials and methods: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry.Results: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n=3), 800 mg bid (n=3), 1600 mg bid (n=6), 2200 mg bid (n=5) and 3000 mg bid (n=3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over three years.Conclusion: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.