Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer.
Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer.
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DOI：
10.1038/sj.bjc.6605798
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发表时间：
2010-08-10
影响因子：
8.8
通讯作者：
Costello, A. J.
中科院分区：
文献类型：
--
作者：
Corcoran, N. M.;Hovens, C. M.;Michael, M.;Rosenthal, M. A.;Costello, A. J.
血管生成是包括前列腺癌在内的许多实体肿瘤发展的基础。硒酸钠是一种小的，水溶性的，口服生物可利用的PP2A磷酸酶活化剂，具有抗血管生成特性。这是一项剂量递增的I期研究，研究对象是无症状、chemotherapy-naïve、去势抵抗性前列腺癌的男性。主要目的是确定最大耐受剂量（MTD）。次要目标包括建立安全性、耐受性和药代动力学特征。共有19名患者入组。MTD为每天60毫克。剂量限制性毒性（疲劳和腹泻）在每天90mg时观察到。在所有治疗队列中，最常见的治疗相关不良事件是恶心、腹泻、疲劳、肌肉痉挛、脱发和指甲疾病。没有观察到4级毒性，研究中没有死亡。观察线性药代动力学。1例患者PSA应答率为50%。到PSA进展的中位时间（无应答者）为14.2周。在主要治疗阶段，平均PSA翻倍时间从试验前的2.18个月增加到3.85个月。硒酸钠的耐受性良好，剂量为每天60毫克，单药疗效中等，与其他抗血管生成药物相似。进一步的试验与传统的细胞毒性方案相结合是有必要的。
Angiogenesis is fundamental to the progression of many solid tumours including prostate cancer. Sodium selenate is a small, water-soluble, orally bioavailable activator of PP2A phosphatase with anti-angiogenic properties. This was a dose-escalation phase I study in men with asymptomatic, chemotherapy-naïve, castration-resistant prostate cancer. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included establishing the safety, tolerability and pharmacokinetic profile. A total of 19 patients were enrolled. The MTD was 60 mg per day. Dose-limiting toxicity (fatigue and diarrhoea) was observed at 90 mg per day. The most frequently reported treatment-related adverse events across all treatment cohorts were nausea, diarrhoea, fatigue, muscle spasms, alopecia and nail disorders. No grade 4 toxicities were observed and there were no deaths on study. Linear pharmacokinetics was observed. One patient had a PSA response >50%. Median time to PSA progression (for non-responders) was 14.2 weeks. Mean PSA doubling time increased during the main treatment phase from 2.18 months before trial to 3.85 months. Sodium selenate is well tolerated at a dose of 60 mg per day with modest single-agent efficacy similar to other anti-angiogenic agents. Further trials in combination with conventional cytotoxic regimens are warranted.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
6.6
作者：
Corcoran, NM;Najdovska, M;Costello, AJ
通讯作者：
Costello, AJ
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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影响因子：
11.2
作者：
Gravdal, Karsten;Halvorsen, Ole J.;Akslen, Lars A.
通讯作者：
Akslen, Lars A.
影响因子：
2.3
作者：
Baade, PD;Coory, MD;Aitken, JF
通讯作者：
Aitken, JF