Arsenic Trioxide and Vitamin C in AML

三氧化二砷和维生素 C 在 AML 中的应用

• 批准号: 6768165
• 负责人: DAN DOUER
• 金额: $ 21.92万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-16 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6768165
• 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

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）：三氧化二砷（As3O2）已在临床试验中显示出对称为急性早幼粒细胞白血病（APL）的急性髓系白血病（AML）亚型具有主要治疗作用。初步体外结果表明，As302 通过多种机制克服细胞对化疗的耐药性，对其他肿瘤（包括非 APL AML、淋巴和骨髓瘤细胞系）具有抗肿瘤活性。一种机制是 As3O2 通过细胞内谷胱甘肽 (GSH) 诱导细胞凋亡并增加活性氧 (ROS) 的产生。谷胱甘肽 (GSH) 水平较低的癌细胞（包括 AML）对 As2O3 诱导的细胞凋亡更敏感，减少细胞内 GSH 的化合物可以诱导或增强 As2O3 的这种作用。多项研究表明，维生素 C/抗坏血酸 (AA) 可以增强 As302 诱导的非 AML、APL AML 和多发性骨髓瘤细胞系的细胞凋亡，这表明 As302 与 AA 联合可能是化疗难治性肿瘤的有效抗肿瘤方法。从迄今为止进行的试点临床研究来看，这种组合的毒性也可能低于强化化疗。因此，As302 加 AA 也可能是一种更安全的替代方法或可能的补充方法，用于治疗不想或不能接受强化常规化疗的非 APL AML 患者。 As302 AA 的体外研究已在极少数非 APL AML 细胞系上进行，但样本是从许多患者身上新鲜获得的。因此，不知道患者之间的差异。因此，我们建议通过诱导细胞凋亡来研究 As302 的体外抗肿瘤活性，并测试 AA 是否可以增强从患者新鲜获得的非 APL AML 细胞上的抗肿瘤活性。我们还将研究 GSH 消耗和 ROS 产生的作用机制。由于 As302 加抗坏血酸组合的 I 期研究已被证明是安全且耐受性良好的，因此我们将进行一项试点 II 期临床试验，以确定该组合对患有非 APL AML 患者的可行性、安全性和可能的​​疗效。已经失败或不会接受化疗。总之，与传统化疗相比，这种联合疗法对非 APL AML 患者可能具有更高的获益/风险比，从而产生更好的总体结果和更低的毒性。