Arsenic Trioxide and Vitamin C in AML

三氧化二砷和维生素 C 在 AML 中的应用

基本信息

批准号：
6886831
负责人：
DAN DOUER
金额：
$ 21.94万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-16 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6886831
关键词：
acute myelogenous leukemia antineoplastics apoptosis arsenic ascorbate bone marrow clinical research clinical trial phase I clinical trial phase II combination cancer therapy flow cytometry free radical oxygen glutathione human subject human therapy evaluation hydrogen peroxide neoplasm /cancer chemotherapy neoplasm /cancer nutrition therapy nutrition related tag oxides patient oriented research pharmacokinetics superoxides

acute myelogenous leukemia antineoplastics apoptosis arsenic ascorbate bone marrow clinical research clinical trial phase I clinical trial phase II combination cancer therapy flow cytometry free radical oxygen glutathione human subject human therapy evaluation hydrogen peroxide neoplasm /cancer chemotherapy neoplasm /cancer nutrition therapy nutrition related tag oxides patient oriented research pharmacokinetics superoxides

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项目摘要

DESCRIPTION (provided by applicant): Arsenic trioxide (As302,) has been shown in clinical trials to have a major therapeutic effect in the acute myeloid leukemia (AML) subtype called acute promyeloctyic leukemia (APL). Preliminary in vitro results have suggested that As302 has antineoplastic activity in other tumors including non-APL AML, lymphoid and myeloma cell lines by several mechanisms that overcome cell resistance to chemotherapy. One mechanism is by As3O2 induced apoptosis via intracellular glutathione (GSH) and increased production of reactive oxygen species (ROS). Cancer cells (including AML) with lower glutathione (GSH) levels are more sensitive to As203 induced apoptosis and compounds that decrease intracellular GSH can induce or increase this effect of As203. Several studies have shown that Vitamin C/ascorbic acid (AA) can enhance As302 induced apoptosis in non-AML APL AML, and multiple myeloma cell lines, suggesting that combining As302 with AA may be an effective antineoplastic approach in tumors refractory to chemotherapy. From pilot clinical studies performed so far, this combination could also be less toxic than intensive chemotherapy. Thus, As302 plus AA could also be a safer alternative or possible complementary approach to treat non-APL AML patients who do not want or cannot be treated with intensive conventional chemotherapy. In vitro studies with As302 AA have been done on very few non-APL AML cell lines but samples freshly obtained from many patients. Thus, no patient-to-patient variability is known. We therefore propose to study antineoplastic activity in vitro of As302 by inducing apoptosis and test if such activity could be enhanced by AA on non-APL AML cells freshly obtained from patients. We will also study the mechanism of action focusing on GSH depletion and ROS production. Since phase I studies of combination of As302 plus ascorbic acid have already been found to be safe and well tolerated we will conduct a pilot phase II clinical trial to determine the feasibility, safety and possible efficacy of the combination in patients with non-APL AML who had failed or will not receive chemotherapy. In summary, this combination may have higher benefit/risk ratio in non-APL AML patients resulting in an overall better outcome with less toxicity than conventional chemotherapy.

描述（由申请人提供）：在临床试验中已显示三氧化物（AS302）在急性髓性白血病（AML）亚型中具有重大治疗作用，称为急性前瞻性白血病（APL）。初步的体外结果表明，AS302通过克服细胞对化学疗法的细胞耐药性的几种机制，包括非APL AML，淋巴样和骨髓瘤细胞系在内的其他肿瘤中具有抗塑性活性。一种机制是通过AS3O2通过细胞内谷胱甘肽（GSH）诱导的凋亡，并增加了活性氧（ROS）的产生。具有较低谷胱甘肽（GSH）水平的癌细胞（包括AML）对AS203诱导的细胞凋亡更敏感，并且降低细胞内GSH的化合物可以诱导或增加AS203的这种影响。几项研究表明，维生素C/抗坏血酸（AA）可以增强AS302在非AML APL AML中诱导的凋亡和多个骨髓瘤细胞系，这表明将AS302与AA结合可能是在肿瘤抑制化学疗法中的有效抗肿瘤方法。从到目前为止进行的试点临床研究中，这种组合的毒性也可能比强化化学疗法更小。因此，AS302 Plus AA也可能是一种更安全的替代方案或可能的补充方法，用于治疗不想要或无法接受强化常规化学疗法治疗的非APL AML患者。对AS302 AA的体外研究已经在很少的非APL AML细胞系上进行，但是从许多患者那里获得的样品。因此，尚无患者到患者的变异性。因此，我们建议通过诱导细胞凋亡并测试AA是否可以通过AA增强这种活性在新近从患者那里获得的非APL AML细胞上增强这种活性来研究AS302的抗肿瘤活性。我们还将研究着重于GSH耗竭和ROS产生的作用机理。由于已经发现AS302 Plus抗坏血酸组合的I阶段研究是安全且耐受性良好的，因此我们将进行II期临床试验，以确定该组合在失败或不会接受化学疗法的非APL AML患者中的可行性，安全性和可能的功效。总而言之，这种组合可能具有比常规化学疗法更低的非APL AML患者的益处/风险率更高，总体毒性较低。