Pharmacologic Ascorbate in Myeloma Treatment: Doses Matter.
Pharmacologic Ascorbate in Myeloma Treatment: Doses Matter.
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DOI：
10.1016/j.ebiom.2017.03.014
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发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
Levine M
中科院分区：
文献类型：
--
作者：
Violet PC;Levine M
抗坏血酸（维生素C）在治疗多发性骨髓瘤和其他恶性肿瘤方面遵循了不透明的路径。在骨髓瘤细胞中，抗坏血酸令人惊讶地耗尽谷胱甘肽和增强三氧化二砷的功效。因为口服1克抗坏血酸会使血浆饱和，所以选择该剂量与砷酸盐。可以预见的是，在小型试验中，既没有好处也没有坏处（Rollig和Illmer，2009; Parrow等人，2013年）。同时，新兴的蛋白酶体抑制剂硼替佐米被抗坏血酸盐抑制，抗坏血酸盐与硼替佐米的硼基团络合。尽管不一致（Perrone等人，2009; Bannerman等人，2011），仍然存在关于抗坏血酸-硼替佐米相互作用的担忧，并且硼替佐米是可能在体内抗坏血酸可降解的少数药剂之一。独立地，药理学抗坏血酸盐已经成为癌症治疗中有希望的化疗剂，但是再次遵循不透明的过程（Parrow等人，2013年）。抗坏血酸在1954年被提出作为抗癌治疗，尽管有令人鼓舞的病例记录，但在两项双盲安慰剂对照试验中没有疗效。抗坏血酸药代动力学，从健康受试者的临床研究，解释了为什么。如在双盲试验中，通过静脉内给药绕过了来自口服摄入的抗坏血酸盐浓度的严格控制，如在记录的病例中（Padayatty等人，2004; Parrow等人，2013年）。只有药理学剂量（即，1 g/kg）的静脉内抗坏血酸盐产生高达25 mM的血浆和细胞外液浓度，后者用作细胞外H2 O2形成的前药（Chen等人，2008年）。在H2 O2+毫摩尔抗坏血酸的情况下，由芬顿型反应形成的活性氧物质杀死癌症，但不杀死正常细胞。通过适当的患者筛选，药理学抗坏血酸盐具有最小的风险（Padayatty等人，2010年）。许多报告记录了抗坏血酸药物在临床前实体瘤模型和I期/早期II期试验中的疗效。
Ascorbic acid (vitamin C) has followed opaque paths in treating multiple myeloma, and other malignancies. In myeloma cells, ascorbate surprisingly depleted glutathione and potentiated arsenate trioxide efficacy. Because oral ascorbate at 1 g produces plasma saturation, this dose was selected with arsenate. Predictably, in small trials there was neither benefit nor harm (Rollig and Illmer, 2009; Parrow et al., 2013). Concurrently, the emerging proteasome inhibitor bortezomib was inhibited by ascorbate, which complexed with bortezomib's boron group. Despite inconsistencies (Perrone et al., 2009; Bannerman et al., 2011), concern remains about ascorbate-bortezomib interaction, and bortezomib is one of few agents that perhaps is ascorbate-inhibitable in vivo.Independently, pharmacologic ascorbate has become a promising chemotherapeutic agent in cancer treatment, but again following an opaque course (Parrow et al., 2013). Proposed as an anticancer treatment in 1954, and despite encouraging case documentation, ascorbate had no efficacy in two double-blind placebo-controlled trials. Ascorbate pharmacokinetics, from clinical studies on healthy subjects, explained why. Tight-control of ascorbate concentrations from oral ingestion, as in the double-blind trials, is by-passed by intravenous administration, as in the documented cases (Padayatty et al., 2004; Parrow et al., 2013). Only intravenous ascorbate at pharmacologic doses,(ie, 1 g/kg) produces up to 25 mM plasma and extracellular fluid concentrations, the latter serving as a pro-drug for extracellular H2O2 formation (Chen et al., 2008). With H2O2+ millimolar ascorbate, reactive oxygen species formed by Fenton-type reactions kill cancer but not normal cells. With proper patient screening, pharmacologic ascorbate has minimal risk (Padayatty et al., 2010). Many reports document efficacy of pharmacologic ascorbate in pre-clinical solid-tumor models and in phase I/early phase II trials.