Abstract
High intravenous doses of vitamin C (ascorbic acid) have been reported to benefit cancer patients, but the data are controversial and there is incomplete knowledge of what physiological mechanisms might be involved in any response. Vitamin C is taken up efficiently by cells expressing SVCT2 transporters and since vascular endothelial cells express SVCT2, we explored the hypothesis that administration of high-dose vitamin C (up to 5 g/kg) to mice might affect vascular endothelial function. A single administration of vitamin C to mice induced time- and dose-dependent increases in plasma concentrations of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), a marker for vascular disrupting effects. Responses were comparable to those for the tumor vascular disrupting agents, vadimezan and fosbretabulin. High-dose vitamin C administration decreased tumor serotonin concentrations, consistent with the release of serotonin from platelets and its metabolism to 5-HIAA. High-dose vitamin C also significantly increased the degree of hemorrhagic necrosis in tumors removed after 24 h, and significantly decreased tumor volume after 2 days. However, the effect on tumor growth was temporary. The results support the concept that vitamin C at high dose increases endothelial permeability, allowing platelets to escape and release serotonin. Plasma 5-HIAA concentrations could provide a pharmacodynamic biomarker for vitamin C effects in clinical studies.
Highlights
The physiological effects of orally administered vitamin C as an antioxidant and in preventing scurvy are well known [1,2,3]
New data for groups of three non-tumor-bearing mice treated with fosbretabulin (25 mg/kg) are shown in Figure 2 and indicate that plasma 5-hydroxyindole acetic acid (5-HIAA) concentrations increase significantly (p < 0.05) at both time points
Tumors removed from mice 24 h after treatment with vitamin C were red in color while tumors from control mice were white; this was similar to what was found previously with vadimezan and other vascular disrupting agents
Summary
The physiological effects of orally administered vitamin C as an antioxidant and in preventing scurvy are well known [1,2,3]. Plasma concentrations of vitamin C in humans following high oral doses are limited by absorption, but intravenous administration can overcome this limitation and lead to millimolar plasma concentrations [4, 5]. Vitamin C at high dose can inhibit tumor growth in mice [6,7,8,9] and early studies reported that administration of vitamin C at high intravenous doses to cancer patients increased survival by more than 5 months [10, 11]. Subsequent clinical studies were conflicting and there is currently no clear resolution of the question of whether high-dose intravenous vitamin C affects patient survival [12]. Progress in our understanding of the action of high-dose vitamin C has been hampered by a lack of appropriate biomarkers for physiological responses to vitamin C
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