Numerous studies explored the efficacy of vitamin C in the treatment of cancer, but their mixed findings caused a great deal of controversy. In 1949, Klenner first suggested the possibility of using vitamin C for the treatment of cancer. In 1952, McCormick asserted that vitamin C has been proposed as a chemotherapeutic agent. Hundreds of articles including an array of in vitro, in vivo, cell culture, animal, and human studies have been published on this topic. As a result, it is believed that vitamin C might have anti-cancer effects (1-3).

Twenty-six years ago, Cameron et al. reported that they increased the time of survival of cancer patients and improved their quality of life by administrating high doses of vitamin C (4). As a result, Pauling and Cameron continuously asserted the effect of vitamin C on cancer. However, Moertel et al. (Mayo Clinic) reported that high-dose vitamin C therapy was not effective against advanced cancer (5). This finding is critical because it may prevent clinicians from using vitamin C for cancer patients.

A critical point of both studies (Cameron et al. and Moertel et al.) is that they used a different administration method, intravenous route in the former and oral route of vitamin C in the latter. Oral absorption of vitamin C cannot achieve plasma concentrations comparable to those obtained by intravenous administration. Moreover, it has been recently reported that vitamin C acts as a toxic agent against cancer cells when given intravenously (6).

Unlike most mammals, human and other primates cannot synthesize vitamin C from glucose due to L-gulonolactone oxidase deficiency. Therefore, we must be obtained adequate amounts of this nutrient from foods and supplements. Vitamin C plays a crucial role in the synthesis of L-carnitine from lysine, neurotransmitters synthesis, cytochrome p-450 activity, cholesterol metabolism, detoxification of exogenous compounds and as an antioxidant (7-10). In addition, when given in large doses, vitamin C may function as an ergogenic agent (11). Because the levels of vitamin C in the blood of the cancer patients were significantly decreased compared to healthy persons, cancer patients required larger amounts of vitamin C (12, 13).

Improved health-related quality of life is important as much as a cure of cancer in terminally ill cancer patients who have an estimated survival of less than 6 months. The objective of this study was to examine changes in the quality of life in terminally ill cancer patients after administration of high-doses of vitamin C.

In terminal cancer patients, the quality of life is as important as cure. The treatment for terminal cancer patients was particularly focused on the patient's well-being in addition to the efforts to minimize symptoms. Thus, the ultimate goal of treatment for terminal cancer patients can differ from those pursued in treatments designed to cure.

If terminal cancer patients were concerned about emotional changes and functional impairment and if the patients' quality of life did not improve, the treatment that they underwent should not be considered successful even though it extended their life expectancy. Although investigators are divided in their opinions on whether vitamin C is effective for the treatment of cancers, many of them reported that cancer patients showed improvement in their quality of life.

This study also demonstrated improvement in global health/quality of life in terminal cancer patients after administration of vitamin C along with improvements in all functions (physical, role, emotional, cognitive, and social) and some symptoms (fatigue, nausea/vomiting, pain, sleep disturbance, and appetite loss).

The therapeutic impacts of vitamin C, expected when administered to terminal cancer patients, include anticancer effects, positive impact on the central nervous system and mental ability, pain relief and contribution to energy generation. The anticancer effects of vitamin C boost cytotoxicity of tumor cells, collagen synthesis, antioxidant action, immunity system and low concentration of certain amino acids. First, the mechanism underlying the action of vitamin C in combating cancer cells explains that vitamin C in blood is oxidized to dehydroascorbate acid, which passes freely back and forth through the cell membranes via glucose transport. When dehydroascorbate acid enters cancer cells, glutathione turned the dehydroascorbate back into ascorbic acid (vitamin C), which is not allowed to move out of cancer cells. This ascorbic acid is converted to dehydroascorbate again and produces H₂O₂, which destroy cancer cells (15). Higher levels of ascorbic acid were observed around cancer cells when compared to normal cells (16). Casciari et al. study reported tumor cells apoptosis occurred in 42.9% of total patients and necrosis in 24.4% when patients' blood level of vitamin C was 11.2 mM. They said apoptosis increased to 57.6% and necrosis to 33.1%, respectively, when patients' blood level of vitamin C rose to 33.7 mM (17). Secondly, an increase in the synthesis of collagen inhibits the growth of cancer cells, leading to apoptosis and necrosis in cancer cells (18). That is, cancer cells releases collagenase and dissove collagen between cells/tissues. This means that these enzymes dissolve basement membranes, an organization of collagen and extracellular matrices, enabling cancer cells to infiltrate and destroy adjacent normal tissues. An increase in collagen synthesis due to vitamin C would however increase membrane mechanical integrity and cohesion and eventually prevent the growth of cancer cells. Thirdly, antioxidant properties of vitamin C inhibit cancer growth induced by free radicals (3, 19). It is however an interesting fact that vitamin C is taken up in oxidized form by cancer cells. Fourthly, vitamin C enhances the immune system by elevating the production of infection-fighting white blood cells and interferon levels, so cancer cells are suppressed or eliminated (20, 21). Last, the vitamin C can change the levels of certain amino acids in body fluids and may deplete the bioavailability of lysine and cyteine, 2 amino acids that required for rapidly growing tumors (22, 23).

The impact of vitamin C on the central nervous system and mental ability is based on the following mechanisms: First, increased c-AMP enables vitamin C to block phosphodiesterase, so the breakdown of c-AMP can be prevented (24). An increase in blood c-AMP levels therefore boosts mental ability. Secondly, vitamin C also prevents the formation of toxic neurotransmitters. Vitamin C deficiency triggers the oxidation of adrenalin and noradrenalin, and adrenochrome and noradrenochrome are generated, respectively, and their toxic effects pose various problems (25).

The impact of vitamin C on pain relief is explained by various mechanisms (26). First, vitamin C has anti-inflammatory effects by stimulating c-AMP production, which in turn elevates production of steroid in the ACTH. Secondly, vitamin C works to help decrease blood calcium levels and enhances calcium uptake in bone. As a result, bone pain is relieved (27).

It was recently discovered that vitamin C also supports the body's energy generation (28). The mechanism of ergogenic activity of vitamin C is probably due to vitamin C's oxidation reduction potential, capable of providing necessary electrons to the electron transport system in the mitochondria for increased energy production.

Since Szent-Gyorgyi reported the efficacy of vitamin C for the first time in 1928, studies in the same area have continued and anticancer effects of vitamin C are still under debate. While Cameron et al. suggested beneficial effects of vitamin C on the treatment of cancer (4), the Mayo Clinic study reported no anticancer effects of vitamin C (5). Investigators cited the different administration method as the reason for such opposite results. The former used intravenous vitamin C administration at a dose of 10 g and subsequent oral administration, whereas the latter used oral administration only. Padayatty et al. proved that it was difficult to increase vitamin C level to more than 220 M/L in blood through oral administration and that blood levels of vitamin C that are required for combating cancer could be achieved through intravenous adminstration (6). Their findings provided the scientific basis for using intravenous administration in cancer patients.

Vitamin C is a water-soluble and remarkably nontoxic at high levels. Nevertheless, this treatment should be administered with caution to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (29). When given high doses of vitamin C, these patients may have the risk of developing hemolysis. Before applying vitamin C therapy, patients should be screened for this deficiency.

Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered the safe and effective therapy to improve the quality of life in terminal cancer patients. The further study is required to compare effects of vitamin C in between placebo and vitamin C group in terminal cancer patients with well-designed experimental strategy.