Arsenic Trioxide & Ascorbic Acid for Multiple Myeloma

描述(申请人提供)：尽管在治疗方面取得了进步，但超过90%的多发性骨髓瘤患者最终会因耐化疗疾病而复发。这些骨髓瘤细胞通常通过一系列不同的机制对多种化疗药物产生耐药性，包括外排泵上调、药物靶点突变和对药物诱导的细胞凋亡的耐药性。因此，开发对多药耐药骨髓瘤有效的新的治疗药物是很重要的。三氧化二砷(As203)最近被证明具有显著的抗复发急性早幼粒细胞白血病活性。我们已经报道As203在体外有效地诱导耐药骨髓瘤细胞系和复发患者的原发骨髓瘤分离株的凋亡。砷诱导的细胞凋亡是通过产生活性氧(ROS)和随后的氧化性细胞损伤来触发的。我们还发现，细胞内谷胱甘肽(GSH)对As203的毒性具有保护作用(通过降低ROS或直接与砷结合)。添加抗坏血酸(AA)可耗尽细胞内GSH，并增强As203介导的对化疗耐药骨髓瘤细胞的杀伤。这些数据使我们开启了一项由NCI赞助的三氧化二砷+抗坏血酸治疗复发和难治性多发性骨髓瘤的I/II期临床试验。我们已经完成了第一阶段的成分，并发现As203剂量为0.25 mg/kg/d+AA 1000 mg/d可以安全地服用，毒性轻微，疗效良好。相关研究表明，血清抗坏血酸水平与细胞内GSH耗竭显著相关。我们的假设是，这种组合将对复发和难治性多发性骨髓瘤具有活性，并提议进行II期临床试验，以确定三氧化二砷+抗坏血酸治疗复发/难治性骨髓瘤的疗效。这项建议的核心部分是相关研究，将寻求建立疗效和毒性的生化、细胞和遗传相关性。此外，我们还将描述骨髓瘤细胞对砷产生抗药性的潜在机制，这种抗药性对其他药物反应的影响，以及克服这种抗药性的方法。

DESCRIPTION (provided by applicant): Despite advances in therapy, greater than 90% of patients with multiple myeloma eventually relapse with chemotherapy-resistant disease. These myeloma cells are typically resistant to a wide range of chemotherapy agents through a number of different mechanisms, including upregulation of efflux pumps, mutations in drug targets and resistance to drug-induced apoptosis. It is therefore important to develop new treatment agents that are active against multi-drug resistant myeloma. Arsenic trioxide (As203) has been recently shown to have significant activity against relapsed acute promyelocytic leukemia. We have reported that As203 effectively induces apoptosis in vitro of both drug resistant myeloma cell lines and primary myeloma isolates from relapsed patients. Arsenic-induced apoptosis is triggered through the generation of reactive oxygen species (ROS) and subsequent oxidative cellular damage. We have also found that intracellular glutathione (GSH) protects against the toxicity of As203 (either by reducing ROS or by direct conjugation to arsenic). Addition of ascorbic acid (AA) depletes intracellular GSH and potentiates As203-mediated killing of chemotherapy-resistant myeloma cells. These data led us to open an NCI-sponsored phase I/II clinical trial of arsenic trioxide + ascorbic acid for the treatment of relapsed and refractory multiple myeloma. We have completed the phase I component, and have found that an As203 dose of 0.25 mg/kg/d + AA 1000 mg/d can be safely administered with modest toxicity and promising efficacy. Correlative studies demonstrate a significant association of serum ascorbic acid levels with depletion of intracellular GSH. Our hypothesis is that this combination will have activity against relapsed and refractory multiple myeloma, and propose a phase II clinical trial to determine the efficacy of arsenic trioxide + ascorbic acid in the treatment of relapsed/refractory myeloma. The central components of this proposal are correlative studies will seek to establish biochemical, cellular and genetic correlates of efficacy and toxicity. In addition, we will characterize potential mechanisms by which myeloma cells become arsenic resistance, the effect of this resistance on responses to other drugs, and approaches to overcome this resistance.