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The effect of L-ascorbate and its derivatives on the growth of malignant and nonmalignant cell lines has been examined. L-Ascorbate and its oxidative product dehydroascorbate were cytotoxic or lethal to the fast-growing malignant cells, but they were less toxic to nonmalignant cells. Two isomers of ascorbate, D-ascorbate and D-isoascorbate, both with 5% of the antiscorbutic potency and very high turnover rate, had similar activities. The cytotoxic effect of ascorbate was apparently not related to the metabolic or vitamin activities of ascorbate at the cellular level. Furthermore, studies on the viability of treated cells indicated that the observed effect on cell growth was not cytostatic in nature but was the result of a direct cell-killing action of ascorbate. Several groups of ascorbate derivatives were also tested; many of them were toxic to these cells. The results support the hypothesis that the cytotoxic activity of ascorbate was due to its chemical properties and that certain oxidation and degradation products of ascorbate were cytotoxic agents.

The growth of human lung carcinoma xenografts implanted beneath the renal capsule of immunocompetent mice was investigated (the six-day subrenal capsule assay) by using combinations of ascorbic acid and cupric ions. A maximum suppression of growth of this human lung tumor, LX-1, was observed at an estimated consumption level by the mice of 6 to 8 g ascorbic acid and 2 to 5 mg cupric ions per day per kg body weight. The data suggest that more than one oxidative or degradative product of ascorbic acid or of some copper compounds may be responsible for the observed antitumor activities, and that the chemotherapeutic effect is being produced at some stoichiometric ratios of ascorbic acid to cupric ions. When such a combination of the two substances was consumed by the mice, optimal therapeutic effect was exerted on the implanted xenografts.

The effect of exogenous ascorbic acid intake on enzymatic formation of ascorbic acid in mice has been studied. After the mice were on diets containing ascorbic acid for two months, the rates of ascorbic acid formation in mouse liver homogenates were measured in vitro using glucuronolactone and gulonolactone as substrate in their respective reaction systems. Exogenous ascorbic acid intake (1, 5 or 8% in the diet) was able to reduce activities of ascorbic acid synthesizing enzymes in mouse liver in either the glucuronolactone or gulonolactone system. The control mechanism for reaction of glucuronolactone to produce ascorbic acid is not stereospecific because large amounts of dietary erythorbic acid, a stereoisomer of ascorbic acid, could also reduce the rate of ascorbic acid formation when glucuronolactone was used as substrate. However, the regulation of ascorbic acid synthesis using gulonolactone as a precursor was apparently stereospecific. Dietary glucose or xylitol had no effect on activities of ascorbic acid synthesizing enzymes.

The effect of ascorbic acid on the growth of human mammary tumor xenografts was investigated using the 6-day subrenal capsule assay method. The results showed that ascorbic acid (1 or 5 g/liter) administered in the drinking water significantly inhibited the growth of tumor fragments implanted beneath the renal capsule of immunocompetent mice. The results agree with other work carried out in animal experiments with animal tumors. Administration of ascorbic acid in the mouse diet did not affect the growth of the human mammary tumor fragments within the 6-day experimental period. Tumor growth was inhibited when mice were fed a diet containing ascorbic acid (50g/kg diet) together with cupric sulfate (18 or 90 mg/liter) in the drinking water. The results support the hypothesis that certain oxidation and degradation products of ascorbic acid are active antineoplastic agents for the human mammary carcinoma studied.