Dachs Gabi U, Gandhi Jamish, Wohlrab Christina, Carr Anitra C, Morrin Helen R, Pullar Juliet M, Bayer Simone B, Eglinton Tim W, Robinson Bridget A, Vissers Margreet C M
Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand.
Department of Surgery, Christchurch Hospital, University of Otago Christchurch, Christchurch, New Zealand.
Front Oncol. 2021 Jan 11;10:600715. doi: 10.3389/fonc.2020.600715. eCollection 2020.
The use of high dose ascorbate infusions in cancer patients is widespread, but without evidence of efficacy. Several mechanisms whereby ascorbate could affect tumor progression have been proposed, including: (i) the localized generation of cytotoxic quantities of HO; (ii) ascorbate-dependent activation of the 2-oxoglutarate-dependent dioxygenases that control the hypoxia-inducible factors (HIFs) and that are responsible for the demethylation of DNA and histones; (iii) increased oxidative stress induced by dehydroascorbic acid. We hypothesize that the dysfunctional vasculature of solid tumors results in compromised delivery of ascorbate to poorly perfused regions of the tumor and that this ascorbate deficit acts as an additional driver of the hypoxic response via upregulation of HIFs. Using a randomized "therapeutic window of opportunity" clinical study design we aimed to determine whether ascorbate infusions affected tumor ascorbate content and tumor biology. Patients with colon cancer were randomized to receive infusions of up to 1 g/kg ascorbate for 4 days before surgical resection ( = 9) or to not receive infusions ( = 6). Ascorbate was measured in plasma, erythrocytes, tumor and histologically normal mucosa at diagnostic colonoscopy and at surgery. Protein markers of tumor hypoxia or DNA damage were monitored in resected tissue. Plasma ascorbate reached millimolar levels following infusion and returned to micromolar levels over 24 h. Pre-infusion plasma ascorbate increased from 38 ± 10 µM to 241 ± 33 µM (p < 0.0001) over 4 days and erythrocyte ascorbate from 18 ± 20 µM to 2509 ± 1016 µM (p < 0.005). Tumor ascorbate increased from 15 ± 6 to 28 ± 6 mg/100 g tissue (p < 0.0001) and normal tissue from 14 ± 6 to 21 ± 4 mg/100 g (p < 0.001). A gradient of lower ascorbate was evident towards the tumor centre in both control and infusion samples. Lower expression of hypoxia-associated proteins was seen in post-infusion tumors compared with controls. There were no significant adverse events and quality of life was unaffected by ascorbate infusion. This is the first clinical study to demonstrate that tumor ascorbate levels increase following infusion, even in regions of poor diffusion, and that this could modify tumor biology.
ANZCTR Trial ID ACTRN12615001277538 (https://www.anzctr.org.au/).
大剂量抗坏血酸静脉输注在癌症患者中的应用很广泛，但尚无疗效证据。已经提出了几种抗坏血酸可能影响肿瘤进展的机制，包括：（i）局部产生具有细胞毒性量的羟基自由基；（ii）抗坏血酸依赖性激活2-氧代戊二酸依赖性双加氧酶，这些酶控制缺氧诱导因子（HIFs），并负责DNA和组蛋白的去甲基化；（iii）脱氢抗坏血酸诱导的氧化应激增加。我们假设实体瘤功能失调的脉管系统导致抗坏血酸向肿瘤灌注不良区域的输送受损，并且这种抗坏血酸缺乏通过上调HIFs而成为缺氧反应的另一个驱动因素。我们采用随机“治疗机会窗口”临床研究设计，旨在确定抗坏血酸静脉输注是否会影响肿瘤抗坏血酸含量和肿瘤生物学特性。结肠癌患者被随机分为两组，一组在手术切除前4天接受高达1 g/kg抗坏血酸的静脉输注（n = 9），另一组不接受输注（n = 6）。在诊断性结肠镜检查时以及手术时，测量血浆、红细胞、肿瘤组织和组织学正常黏膜中的抗坏血酸含量。在切除的组织中监测肿瘤缺氧或DNA损伤的蛋白质标志物。静脉输注后血浆抗坏血酸达到毫摩尔水平，并在24小时内恢复到微摩尔水平。输注前4天血浆抗坏血酸从38±10 μM增加到241±33 μM（p < 0.0001），红细胞抗坏血酸从18±20 μM增加到2509±1016 μM（p < 0.005）。肿瘤抗坏血酸从15±6增加到28±6 mg/100 g组织（p < 0.0001），正常组织从14±6增加到21±4 mg/100 g（p < 0.001）。在对照和输注样本中，均可见向肿瘤中心抗坏血酸含量降低的梯度。与对照组相比，输注后肿瘤中缺氧相关蛋白的表达较低。没有明显的不良事件，抗坏血酸静脉输注未影响生活质量。这是第一项临床研究，证明即使在扩散不良的区域，静脉输注后肿瘤抗坏血酸水平也会升高，并且这可能会改变肿瘤生物学特性。
澳大利亚和新西兰临床试验注册中心试验编号ACTRN12615001277538（https://www.anzctr.org.au/）。
