Arsenic Trioxide and Vitamin C in AML

描述（由申请人提供）：三氧化二砷（As302）已在临床试验中显示对急性早幼粒细胞白血病（APL）具有主要治疗作用。初步的体外实验结果表明，As302在其他肿瘤（包括非apl AML、淋巴细胞和骨髓瘤细胞系）中具有抗肿瘤活性，其机制可以克服细胞对化疗的耐药性。其中一种机制是As3O2通过细胞内谷胱甘肽（GSH）和活性氧（ROS）的增加诱导细胞凋亡。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，而降低细胞内谷胱甘肽（GSH）的化合物可以诱导或增加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细胞凋亡，提示As302联合AA可能是化疗难治肿瘤的有效抗肿瘤途径。从目前进行的初步临床研究来看，这种组合也可能比强化化疗的毒性更小。因此，As302 + AA也可能是一种更安全的替代或可能的补充方法，用于治疗不希望或不能接受强化常规化疗的非apl AML患者。As302 AA的体外研究已经在很少的非apl AML细胞系上进行，但从许多患者身上新鲜获得的样本。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在体外的抗肿瘤活性，并测试AA是否可以增强As302对新鲜获得的非apl AML细胞的抗肿瘤活性。我们还将重点研究GSH消耗和ROS产生的作用机制。由于As302联合抗坏血酸的I期研究已经被发现是安全且耐受性良好的，我们将进行一项II期临床试验，以确定该联合治疗化疗失败或不接受化疗的非apl AML患者的可行性、安全性和可能的疗效。总之，与传统化疗相比，这种联合治疗在非apl AML患者中可能具有更高的获益/风险比，总体结果更好，毒性更小。

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.