A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.
A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia.
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DOI：
10.1016/j.ebiom.2015.11.025
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发表时间：
2015-12
期刊：
影响因子：
11.1
通讯作者：
Malafa MP
中科院分区：
文献类型：
--
作者：
Springett GM;Husain K;Neuger A;Centeno B;Chen DT;Hutchinson TZ;Lush RM;Sebti S;Malafa MP
维生素E δ-生育三烯酚（VEDT）是一种来自植物的天然维生素E，在胰腺癌临床前模型中显示出抗肿瘤和化学预防活性。在这里，我们调查了VEDT在胰腺导管肿瘤患者的机会窗口术前临床试验，以评估其安全性，耐受性，药代动力学和凋亡活性。患者在手术前13天每天接受递增剂量（200至3200 mg）的口服VEDT，并在手术当天接受一剂。剂量递增遵循3 + 3试验设计。我们的主要终点是安全性、VEDT药代动力学和监测VEDT诱导的肿瘤细胞凋亡（ClinicalTrials.gov编号NCT00985777）。在25例接受治疗的患者中，未出现剂量限制性毒性;因此未达到最大耐受剂量。1例患者在3200 mg每日剂量水平下发生药物相关不良事件（腹泻）。VEDT的有效半衰期约为4 h。血浆中的VEDT浓度和暴露曲线变化很大，但达到了临床前模型中的生物活性水平。在400 mg至1600 mg每日剂量水平下，在大多数患者中观察到生物活性，定义为通过增加裂解的半胱天冬酶-3水平测量的肿瘤细胞凋亡的显著诱导。VEDT从200至1600毫克，每天口服胰腺手术前2周，耐受性良好，达到血液中的生物活性水平，并显着诱导胰腺导管肿瘤患者的肿瘤细胞凋亡。这些有希望的结果保证了VEDT用于胰腺癌的化学预防和/或治疗的进一步临床研究。维生素E δ-生育三烯酚是一种天然维生素E的生物活性形式，具有抗癌细胞的活性。维生素E δ-生育三烯酚在高达3200 mg的患者中是安全的。与正常细胞相比，维生素E δ-生育三烯酚在400、600和800 mg/天时选择性地杀死胰腺肿瘤细胞。维生素E δ-生育三烯酚的生物标志物效应表明在患者中具有显著的抗癌活性，维生素E对人类来说是一种有趣的维生素，因为它有促进人类健康的潜力。然而，用维生素E预防癌症的大规模研究结果喜忧参半。由于最近的实验室研究表明，以前用于降低癌症风险的干预措施中使用的维生素E形式不是维生素E的活性生育三烯酚形式，因此存在一个问题，即缺乏维生素活性是否是由于在临床试验中使用非活性形式的维生素E。基于我们的实验室数据，这些数据表明维生素E的维生素E δ-生育三烯酚（VEDT）形式对胰腺癌有活性，我们使用机会窗设计测试了VEDT杀死患者胰腺肿瘤细胞的能力，并将细胞凋亡的测量作为中间终点。我们发现，VEDT在术前2周服用高达3200 mg时耐受性良好。我们还发现，在400至800毫克的剂量下，VEDT选择性地杀死胰腺肿瘤细胞。
Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer. Vitamin E δ-tocotrienol is the bioactive form of one of the natural vitamin E with activity against cancer cells Vitamin E δ-tocotrienol is safe in patients up to 3200 mg Vitamin E δ-tocotrienol selectively kills pancreatic tumor cells when compared with normal cells at 400, 600, and 800 mg/day The biomarker effect of vitamin E δ-tocotrienol suggest significant anticancer activity in patients, justifying further study Vitamin E has been an intriguing vitamin to humans for its potential to promote human health. However, large-scale research with vitamin E to prevent cancer has had mixed results. Because recent laboratory studies have shown that the form of vitamin E used in previous interventions to reduce cancer risk have not been the active tocotrienol form of vitamin E, there is a question as to whether the lack of vitamin activity is due to the use of inactive forms of vitamin E in clinical trials. Based on our laboratory data, which showed that the vitamin E δ-tocotrienol (VEDT) form of vitamin E was active against pancreatic cancer, we tested the ability of VEDT to kill pancreatic tumor cells in patients using a window-of-opportunity design, with measurement of apoptosis as an intermediate endpoint. We found that VEDT was well tolerated at up to 3200 mg when taken for 2 weeks before surgery. We also found that, at doses of 400 to 800 mg, VEDT selectively killed pancreatic tumor cells.