Abstract
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 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; (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 (n = 9) or to not receive infusions (n = 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.Clinical Trial RegistrationANZCTR Trial ID ACTRN12615001277538 (https://www.anzctr.org.au/).
Highlights
The use of high dose vitamin C infusions as a complementary therapy for cancer is widespread [1], despite a lack of robust evidence for efficacy
Our study of patients with colon cancer shows that ascorbate concentrations are lower in the tumor core than in the periphery
Administration of ascorbate by intravenous infusions over 4 days prior to surgical resection resulted in supraphysiological plasma concentrations and compartmentalization of high ascorbate concentrations into erythrocytes
Summary
The use of high dose vitamin C (ascorbate) infusions as a complementary therapy for cancer is widespread [1], despite a lack of robust evidence for efficacy. Intravenous ascorbate administration bypasses uptake regulation in the gastrointestinal tract and results in dose-dependent increases in plasma levels, even in excess of 20 mM [4, 6,7,8]. These levels are not maintained following infusion and ascorbate is cleared with a half-life of < 2 h [4, 6,7,8]. That this difference in pharmacokinetics may be critical for a potential anticancer effect remains much discussed, as case studies suggesting a clinical benefit from ascorbate infusions continue to surface [9,10,11,12,13,14,15,16,17]
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