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: 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
• 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

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(申请人提供)：三氧化二砷(As302)已在临床试验中被证明对称为急性早幼粒细胞白血病(APL)的急性髓系白血病(AML)亚型有主要疗效。初步的体外实验结果表明，As302对包括非APL AML、淋巴组织和骨髓瘤细胞系在内的其他肿瘤细胞株具有抗肿瘤活性，其机制可能是通过多种机制来克服细胞对化疗的耐药性。一种机制是As3O2通过细胞内谷胱甘肽(GSH)和增加活性氧(ROS)的产生而诱导细胞凋亡。谷胱甘肽(GSH)水平较低的癌细胞(包括AML)对As203诱导的细胞凋亡更敏感，降低细胞内GSH的化合物可以诱导或增强As203的这种作用。多项研究表明，维生素C/抗坏血酸(AA)可增强As302诱导的非AML、APL AML和多发性骨髓瘤细胞系的凋亡，提示As302联合AA可能是治疗化疗无效肿瘤的一种有效的抗肿瘤方法。从到目前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，对于不想或不能接受强化常规化疗的非APL AML患者，As302加AA也可能是一种更安全的替代或可能的补充方法。As302 AA的体外研究已经在极少数非APL AML细胞系上进行，但从许多患者的新鲜样本中获得。因此，患者之间的变异性是未知的。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细胞的这种活性。我们还将重点研究GSH耗竭和ROS产生的作用机制。由于As302联合抗坏血酸的第一阶段研究已经被发现是安全和耐受性良好的，我们将进行第二阶段的试点临床试验，以确定联合应用于化疗失败或不接受化疗的非急性早幼粒细胞白血病患者的可行性、安全性和可能的疗效。综上所述，在非急性早幼粒细胞白血病患者中，这种联合治疗可能具有更高的受益/风险比，从而导致总体上比传统化疗更好的结果，毒性更小。