Vitamin C administration by intravenous infusion increases tumour ascorbate content in patients with colon cancer: a clinical intervention study

Abstract

Background: The use of high dose ascorbate infusions in cancer patients is widespread, but without evidence of efficacy. Several mechanisms whereby ascorbate could affect tumour progression have been proposed, including (i) the localised generation of cytotoxic quantities of H2O2, (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 and (iii) increased oxidative stress induced by dehydroascorbic acid. We hypothesise that the dysfunctional vasculature of solid tumours results in compromised delivery of ascorbate to poorly perfused regions of the tumour and that this ascorbate deficit acts as an additional driver of the hypoxic response via upregulation of HIFs. Using a randomised ‘therapeutic window of opportunity’ clinical study we aimed to determine whether ascorbate infusions affected tumour ascorbate content and tumour biology.Methods: Patients with colon cancer were randomised to receive infusions of up to 1 g/kg ascorbate for four days before surgical resection (n=9) or to not receive infusions (n=6). Ascorbate was measured in plasma, erythrocytes, tumour and histologically normal mucosa at diagnostic colonoscopy and at surgery. Protein markers of tumour hypoxia or DNA damage were monitored in resected tissue.Results: Plasma ascorbate reached millimolar levels following infusion and returned to micromolar levels over 24 h. Pre-infusion plasma ascorbate increased from 38 ± 10 mM to 241 ± 33 mM (p<0.0001) over four days and erythrocyte ascorbate from 14 ± 15 mM to 2004 ± 814 mM (p<0.005). Tumour ascorbate increased from 15 ± 6 to 28 ± 6 mg/100g tissue (p<0.0001) and normal tissue from 14 ± 6 to 21 ± 4 mg/100g (p<0.001). A gradient of lower ascorbate was evident towards the tumour centre in both control and infusion samples. Lower expression of hypoxia-associated proteins was seen in post-infusion tumours compared with controls. There were no significant adverse events and quality of life was unaffected by ascorbate infusion.Conclusions: This is the first clinical study to demonstrate that tumour ascorbate levels increase following infusion, even in regions of poor diffusion, and that this could modify tumour biology. Trial registration: ANZCTR Trail ID ACTRN12615001277538

High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients

“…What makes vitamin C interesting as antitumor agent is that it selectively kills cancer cells, without harming normal cells [ 46 , 65 , 67 , 68 , 91 , 159 , 160 ]. This is confirmed by the results of clinical studies indicating that high-doses of vitamin C are generally well tolerated [ 57 , 60 , 62 , 64 , 133 , 161 ].…”

“…Nevertheless, since HIF positively regulates GLUT1 expression, this might favor the entry of DHA into VHL-defective cells sensitizing them to vitamin C cytotoxic effects [ 119 , 132 ]. Interestingly, administration of ascorbate by intravenous infusion to colon cancer patients resulted in increased ascorbate content within the tumor and reduced expression of HIF-dependent proteins [ 133 ].…”