Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Intravenous vitamin C may produce plasma concentrations as high as 15 000 µmol/L. At extracellular concentrations greater than 1000 µmol/L, vitamin C is toxic to cancer cells.

 Case studies suggest that vitamin C, given intravenously at doses of 10-100 grams/day can improve patient well being and in some cases, reduce tumor size. While ascorbate is generally considered safe, clinical data on high intravenous doses is limited. Twenty-four late stage terminal cancer patients were given continuous infusions of 150 to 710 mg/kg/day for up to eight weeks. Blood chemistry and blood count profiles were obtained at roughly one-week intervals while patient health, adverse events and tumor progression were monitored. The majority of patients were vitamin C deficient prior to treatment. Intravenous infusions increased plasma ascorbate concentrations to a mean of 1.1 mM. The most common adverse events reported were nausea, edema, and dry mouth or skin; and these were generally minor. Two Grade 3 adverse events ‘possibly related’ to the agent were reported: one patient with a history of renal calculi developed a kidney stone after thirteen days of treatment and another patient experienced hypokalemia [low potassium] after six weeks of treatment. White blood cell counts were stable while hemoglobin and hematocrit levels dropped slightly during treatment, consistent with trends observed prior to therapy. Blood creatinine, BUN, glucose, and uric acid concentrations decreased or remained stable during therapy, suggesting that ascorbate infusions did not adversely affect renal function. These data suggest that intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation.

British Journal of Cancer (2001) 84(1 1), 1544-1550 

Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours

A recent study* at the University of Nebraska indicates that blood count and chemistry parameters are relatively stable in terminal cancer patients given continuous infusions of up to 50 grams per day [of vit C] for 
up to 8 weeks. 
(*manuscript in preparation. Casciari JJ, Tempeso MA, Riordan NH. Rodrigues G. Taylor P. Jackson JA et al) 

Vitamin C                   Flow cytometry analysis              Surviving 
concentration      Viable    Apoptotic     Necrotic        fraction 
Control                    63.4%        22.2%           14.3%             1.OO 
3.74 mM                 50.6%        29.3%           20.1%               0.84 
11.2 mM                 32.8%        42.9%           24.4%               0.63 
33.7 mM                   9.2%        57.6%           33.1%               0.25 
101 mM                    0.9%        77.6%           21.6%               0.00 

The results presented above lead to 4 major conclusions. First, sodium ascorbate increases the percentage of apoptotic [natural death] and necrotic [induced death] tumor cells in SW620 HFST, though the concentrations necessary for significant cell killing may not be clinically feasible. Second, lipoic acid enhances the anti-tumor efficacy of ascorbate to the point where significant tumour cell killing can occur at 
concentrations achievable by intravenous infusion. Third, the antioxidants lipoic acid, vitamin K₃, and phenyl ascorbate are effective against SW620 HFST in the millimolar range, suggesting their potential use as anticancer agents.

The LC₅₀ value of phenyl-ascorbate, a lipophilic vitamin C analogue, was roughly 3 times lower than that of the parent compound, suggesting that lipophilic ascorbate analogues may be useful and that lipophilic drug delivery systems may improve ascorbate efficacy. When combined with vitamin C, phenyl ascorbate increased efficacy in an additive fashion. SW620 HFST tumors were very sensitive to vitamin K₃. In the combination treatment, vitamin K₃ decreased the ascorbate LC₅₀ by roughly a factor of 4, though 
we could not demonstrate synergy. Most interesting were the results with lipoic acid. DL-a-lipoic acid (DL-6,8-thioctic acid) is a lipophilic antioxidant that can be readily obtained commercially in clinical or research reagent grade. 

Using a 10:1 ratio of ascorbate to lipoic acid decreased the ascorbate LC₅₀, to 4.5 + 0.9 mM. This 
combination killed 25% of SW620 HFST cells at an ascorbate concentration of 1.3 mM.

Lipoic acid, unlike ascorbate, was equally effective against both proliferating and confluent cell monolayers, 
suggesting that lipoic acid may target quiescent cells that are resistant to vitamin C.

Several mechanisms have been proposed by which vitamin C may be useful in treating cancer, including speculation that it improves immune response, reduces the severity of cachexia [weight loss], and strengthens extracellular matrix against tumour cell invasion (Cameron et al, 1979; Henson et al, 1991 ). The ability of ascorbate to kill tumour cells preferentially through hydrogen peroxide generation has been confirmed in several in vitro studies (Bram et al. 1980; Leung et at, 1993) (Benade et al. 1969; Riordan et al. 1995). Rodent studies indicate that ascorbate supplementation can inhibit tumour growth in vivo (Tsao et al, 1988; Varga and Airoldi, 1983). 
The high concentrations of ascorbate needed for significant cell killing led to our interest in combining it with other antioxidants. Previous reports suggest a synergistic relationship between vitamins C and K₃, two hydrogen peroxide generators, using a 100:1 molar ratio against tumour cell monolayers (Noto et al, 1989). 
Lipoic acid is a lipophilic antioxidant that, among other things, inhibits hydrogen peroxide generation by ascorbate in erythrocytes (Ou et al, 1995). We were thus surprised to find that not only was lipoic acid toxic to tumour cells at millimolar concentrations, but that it enhanced the cytotoxicity of ascorbate in a synergistic 
fashion. The reason for this synergy is unknown. Chemically, it may relate to the ability of these nutrients to modify cellular oxidation-reduction status in a manner that enhances H₂O₂ [hydrogen peroxide] toxicity (Jonas et al, 1989) or to possible ascorbate recycling by lipoic acid in redox reactions. Biologically, the effectiveness of lipoic acid in confluent cell monolayers suggests that it may aid in killing non-proliferating SW620 HFST cells that are relatively resistant to ascorbate. 

One key in assessing the value of ascorbate anti-cancer agent is to compare the concentrations required for tumour cell killing with those that can be safely achieved in the clinic. In the case of ascorbate, we found that intravenous infusions of 30 to 60 grams could provide plasma ascorbate exposures that would be effective against SW620 HFST if lipoic acid were also present.

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