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Y Vltamlns In recent years, there has been considerable interest in the role of vitamins A, C, and E in the genesis and prevention of cancer. In contrast, little attention has been paid to the B vitamins and others such as vitamin K. The evidence concerning vitamins A, C, E, and selected B vitamins is discussed below. VITAMIN A Of the entire collection of chemically diverse substances classi- fied as vitamins, those subsumed under the general term vitamin A are of the greatest current interest in terms of their possible association with the process of carcinogenesis. The only well-understood function of vitamin A is its role in the visual cycle. The involvement of this vitamin in cell differentiation, although less well documented, pro- vides a rational basis for examining its relationship to cancer. Ingested vitamin A is absorbed in the bloodstream and stored in the liver, and can reach toxic levels if large amounts are consumed. Blood levels of vitamin A are regulated by a feedback mechanism, but they do not usually reflect the amounts consumed in the diet or stored in the liver. Epidemiological Evidence The impact of vitamin A on carcinogenesis is of considerable interest. Several epidemiological investigations, mostly case-control studies, have indicated an inverse relationship between vitamin A intake and a variety of cancers. With few exceptions, the estimates of vitamin A were based on frequency of ingestion of a group of foods (e.g., green and yellow vegetables) known to be rich in 6-carotene (a provitamin that may be enzymatically converted to vitamin A In vivo) and a few foods such as whole milk and liver containing preformed retinal (vitamin A). Thus, to a large extent, these studies have measured indirect indices of 6-carotene intake. In this discussion the term vitamin A will also be used to include 6-carotene, since the two components are not distinguished in most of the reports. Lung. Bjelke (1975) was one of the first investigators to report epidemiological data suggesting that vitamin A plays a protective role against cancer. Using frequency data collected by a questionnaire 138 9 -1

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Vitamins 139 mailed to a cohort of Norwegian men, he derived a vitamin A index based on limited sources of the vitamin. He observed lower values for lung cancer cases than for controls after controlling for cigarette smoking. MacLennan et al. (1977) found an inverse association between consumption of green, leafy vegetables rich in vitamin A and lung cancer in a case-control study among Chinese females in Singapore. In a case-control study conducted by Gregor et al. (1980), hospital outpatients, mostly from a rheumatology clinic, were used as controls. These investigators found that significantly less vitamin A had been consumed by male lung cancer cases than by controls, mainly because cases had consumed fewer vitamin A supplements and less liver. The few female cases had a different proportional distribution of tumor cell type than the males and showed an opposite (direct) overall association with vitamin A intake, although they also consumed fewer vitamin A supplements than the controls. The use of vitamin A supplements was inversely associated with cancer, including lung cancer, in men (but not women) in a case-control study reported by Smith and Jick (1978~. Mettlin et al. (1979) reported results of a case-control study in which an index of vitamin A consump- tion, based on frequency of consumption of a group of food items, was inversely associated with lung cancer in males, after controlling for cigarette smoking. In 28 patients with bronchial carcinoma, plasma levels of vitamin A were lower than those in a small group of controls (Basu et al., 1976; Sakula, 1976~. Shekelle et al. (1981) reported the findings of a 19-year follow- up study of 1,954 men in Chicago. Lung cancer incidence was inversely associated with carotene intake both with and without adjustment for cigarette smoking. There was no significant association of lung cancer with the intake of preformed vitamin A. Larynx. Graham et al. (1981) studied male cases of laryngeal can- cer and controls. After controlling for cigarette smoking and alcohol consumption, they found an inverse relationship (with a dose-response gradient) between cancer risk and indices of both vitamins A and C in- take based on frequency of consumption of selected foods. They reported similar results for vegetable consumption in general, but not for cru- ciferous vegetables in particular. Bladder. In a case-control study designed like the one conducted on lung cancer, Mettlin _ al. (1979) reported a similar inverse asso- ciation of a vitamin A consumption index with bladder cancer, after controlling for coffee consumption, smoking, and occupational exposure. Esophagus. Wynder and Brass (1961) reported that frequencies of consumption of milk, and of green and yellow vegetables (sources of vitamin A and 6-carotene, respectively) were lower for esophageal cancer cases than for controls. Mettlin et al. (1981) reported a 9 - 2

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140 DIET, NUTRITION, AND CANCER similar inverse association and a dose-response gradient for frequency of consumption of fruits and vegetables in a study of male cases and controls, after controlling for cigarette smoking and alcohol consump- tion. Although they also found an inverse relationship for an index of vitamin A consumption based on selected foods, there was an even stronger inverse relationship for an index of vitamin C consumption. Also consistent with these findings were observations of populations in the Caspian littoral of Iran (a region of particularly high esophageal cancer incidence) indicating that consumption of green vegetables and fresh fruit and estimated vitamin A and C intake in high risk areas were lower than in areas of low risk (Hormozdiari et al., 1975; Joint Iran-International Agency for Research on Cancer Study Group, 1977~. In a subsequent case-control study in this region, investigators also found that cases had consumed smaller amounts of uncooked vegetables (as well as fruits) than had controls (Cook-Mozaffari, 1979; Cook- Mozaffari _ al., 1979~. Stomach. Among other findings, Hirayama (1967) reported an inverse association between daily consumption of milk (a vitamin A source) and stomach cancer in a case-control study in Japan. More recently, Hirayama (1977) reported a similar protective effect of milk based on data from a prospective cohort study involving 265,118 subjects. There was also a lower risk for stomach cancer among non- smokers who consumed green and yellow vegetables. Graham et al. (1972) reported higher consumption of uncooked vegetables {rik~ly sources of 6-carotene) by controls than by cases in a case-control study of gastric cancer in New York State. A simi- lar inverse association with consumption of raw vegetables was noted by Haenszel et al. (1972) in a case-control study in Hawaii. Colon/Rectum. In ongoing cohort studies in Norway and Minnesota, Bjelke (1978) has found that milk and several vegetables have been consumed with less frequency by colorectal cancer cases than by controls. An index of vitamin A intake (which was highly correlated with consumption of vegetables) showed the same inverse relationship. Prostate. In a study on prostate cancer, Schuman et al. (1982) found that foods rich in vitamin A (e.g., liver) and 6-carotene (e.g., carrots) were consumed less frequently by cases than by controls. General. In three recent reports based on data from cohort studies in the United States and England, the investigators observed that there was an inverse relationship between serum levels of vitamin A and sub- sequent risk of cancer in general (Cambien et al., 1980; Kark et al., 1980; Wald _ al., 1980~. The relationship between dietary intake of vitamin A and its level in serum (which is under homeostatic control) is not yet clear in populations such as these, which are generally not deficient in this nutrient. 9 - 3

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Vitamins 141 Experimental Evidence In the following discussion, the term vitamin A is used to include: vitamin A itself, synthetic analogues of vitamin A called retinoids, and naturally occurring plant constituents, the carote- noids, which can be converted to vitamin A in viva. Vitamin A is necessary for normal differentiation of epithelial cells in many tissues. A deficiency of this vitamin results in metaplasia, a pathological condition in which a keratinizing squamous epithelium replaces the form of epithelium that is normal to various tissues (Wolbach and Howe, 1925~. In the bronchial mucosa, for ex- ample, the mucus-secreting columnar epithelium is replaced by a stratified squamous epithelium. Of relevance to the relationship between vitamin A and cancer is the occurrence of metaplasia, early in the evolution of many neoplasms. In the tissue undergoing malig- nant transformation, the normal differentiation pattern is lost and a new form of epithelium appears. Vitamin A Deficiency. Since the appearance of metaplasia is common to both vitamin A deficiency and early neoplasia, a defi- ciency of this vitamin might enhance the neoplastic response to chemical carcinogens. In vitro experiments in organ cultures have supported this concept. In an organ culture of mouse prostatic tissue, vitamin A was shown to prevent the induction of metaplasia induced either by a culture medium deficient in vitamin A or by carcinogenic polycyclic aromatic hydrocarbons (Lasnitzki, 1963~. In organ cultures of hamster tracheas, vitamin A inhibited the induction of squamous cell metaplasia and proliferative epithelial lesions by benzo~a~pyrene (Cracker and Sanders, 1970~. Some _ viva experiments have produced similar results. For ex- ample, Nettesheim and Williams (1976) reported that the induction of neoplastic lesions of the lungs by 3-methylcholanthrene was enhanced in rats deprived of vitamin A intake. This conclusion was based on observations of squamous nodules in the lungs, which have been demon- strated to be precursors of squamous cell carcinomas. Vitamin A de- ficiency also affects the mucosa of the urinary bladder, producing squamous cell metaplasia as well as a high incidence of cystitis, ureteritis, and pyelonephritis. The effects of vitamin A defi- ciency have been investigated in rats given N-~4-~5-nitro-2-furyl)- 2-thiazolyl]-formamide (FANFT), a compound that causes cancer of the bladder. In Sprague-Dawley rats maintained on a diet deficient in vitamin A, there was an acceleration in the neoplastic response to FANFT, resulting in an earlier appearance of urinary bladder tumors and the development of ureteral and pelvic carcinomas (Cohen et al., 1976). Although squamous cell metaplasia in the mucosa of the large bowel does not occur with vitamin A deficiency, several studies have been 9 - 4

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142 DIET, NUTRITION, AND CANCER conducted to determine the effect of such a deficiency on carcinogen- induced neoplasia of the large bowel in the rat (Narisawa et al., 1976; Newberne and Rogers, 1973; Rogers et al., 1973~. Rogers et al. (1973) studied the effects of a low vitamin A intake on response of rats to intragastric administration of 1,2-dimethylhydrazine. They observed a slight increase in the incidence of tumors of the large bowel in the animals on the low vitamin A diet. Different results were obtained by Narisawa _ al. (1976), who administered the carcinogen N-methyl-N'-_ nitro-N-nitrosoguanidine (MNNG) intrarectally to rats. In this study, animals fed a diet free of vitamin A developed fewer neoplastic lesions of the large bowel than those supplemented with vitamin A or fed a commercial chow diet with adequate vitamin A content. An experiment of a somewhat different nature was conducted by Newberne and Rogers (1973~. In this study, rats were exposed to the carcinogen aflatoxin and were fed diets containing various amounts of vitamin A. Animals deficient in vitamin A developed tumors of the large bowel, whereas rats fed a diet containing adequate amounts of vitamin A did not. Neoplasms of the liver developed in both groups of animals; however, there were fewer liver tumors in the group deficient in vitamin A. Thus, the overall effect was a shift in site of neo- plasms rather than an overall change in tumor incidence (Newberne and Rogers, 1973~. In summary, studies in animals indicate that a deficiency of vitamin A can result in an increased susceptibility to carcinogen- induced neoplasia; however, there are exceptions. Excess Intake of Vitamin A. Investigations have also been con- ducted to determine the effect of excess vitamin A on the occurrence of neoplasia in animals. Saffiotti _ al. (1967) demonstrated that a high intake of vitamin A protected against benzo~aipyrene-induced metaplasia and squamous cell neoplasms of the tracheobroncial tree in hamsters. Supporting data reported by Nettesheim and Williams (1976) indicated that vitamin A protects against 3-methylcholanthrene-induced squamous cell metaplasia and early neoplastic lesions of the lung in rats. In contrast, Smith et al. (1975) observed that an intake of high levels of vitamin A increases the incidence of respiratory tract tumors in ham- sters. Retinyl acetate has also been shown to enhance hormone-induced mammary tumorigenesis in female GR/A mice (Welsch et al., 1981~. In studies of other target sites, Chu and Malmgren (1965) and Shamberger (1971) observed that a high intake of vitamin A inhibited formation of tumors of the forestomach and cervix in hamsters and the skin of mice. Rogers et al. (1973) reported that the induction of neoplasia in the large bowel of rats by 1,2-dimethylhydrazine (DMH) was slightly enhanced by a high intake of the vitamin. To summarize, studies in animals indicate that an increased intake of this vitamin has a protective effect against the induction of cancer by chemical carcinogens in most, but not all, instances. 9 - 5

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Vitamins 143 Retinoids. Results from the studies of vitamin A have stimulated efforts to find analogues with a greater inhibitory effect on neoplasia, less toxicity, and a capability of reaching target tissues in concentra- tions higher than those of the naturally occurring vitamin. Many such compounds, the retinoids, have been synthesized, but are not normal con- stituents of the diet. Experiments to study the inhibition of carcino- gen-induced neoplasia of the breast, urinary bladder, skin, and lung by these analogues have produced impressive results (see review by Sporn and Newton, 1979, 1981; Sporn et al., 1976~. These compounds have also been responsible for regression of skin papillomas in mice (Bollag, 1971~. The effects of these compounds buttress observations from studies of naturally occurring vitamin A. Carotenoids. In plants there is a group of compounds, the carote- noids, that can be converted into vitamin A In viva. These compounds can also be absorbed unchanged from the gastrointestinal tract and exist in tissues in their original form. In a recent review of epi- demiological data on vitamin A and related compounds, Peto et al. (1981) considered the possibility that 6-carotene itself rather than its derivative, vitamin A, may have the capacity to inhibit carcino- genesis in epithelial cells. Only a few studies have been conducted to investigate the effects of carotenoids on neoplasia in laboratory animals. Recently, Mathews-Roth et al. (1977) observed that 6-caro- tene, canthaxanthin (4-4'-diketo-6 -carotene), and phytoene can produce a significant protective effect against the development of UV-induced skin tumors in hairless mice. Since canthaxanthin and phytoene are carotenoids that do not have vitamin A activity, the protective effect appears to reside in the carotenoid structure per se. In an earlier study, Shamberger (1971) reported experiments in which 6-carotene applied to the skin of mice concomitantly with croton oil increased the formation of epidermal tumors previously initiated by 7,12-dimethylbenz- [aJanthracene (DMBA). Considerable further research is necessary to evaluate the effects of carotenoids on carcinogenesis in laboratory animals. Summary Epidemiological Evidence. A growing accumulation of epidemiologi- cal evidence indicates that there is an inverse relationship between the risk of cancer and the consumption of foods containing vitamin A (e.g., liver) or its precursors (e.g., some carotenoids in dark green and deep yellow vegetables). Most of the data, however, do not show whether the effects are due to carotenoids, to vitamin A itself, or to some other constituents of these foods. In these studies, investigators found an inverse association between estimates of vitamin A intake and carcinoma at several sites, e.g., the lung, the urinary bladder, and the larynx. All these cancers involve epithelial cells. Experimental Evidence. Studies in animals indicate that vitamin A deficiency generally increases susceptibility to chemically induced 9_b

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144 DIET, NUTRITION, AND CANCER neoplasia, and that an increased intake of the vitamin appears to pro- tect against carcinogenesis in most, but not all, cases. Because high doses of vitamin A are toxic, many of these studies have been conducted with its synthetic analogues, retinoids, which lack some of the toxic effects of the vitamin. These analogues have been shown to inhibit chemically induced neoplasia of the breast, urinary bladder, skin, and lung. Conclusion The committee concluded that the laboratory evidence shows that vitamin A itself and many of the retinoids are able to suppress chemi- cally induced tumors. The epidemiological evidence is sufficient to suggest that foods rich in carotenes or vitamin A are associated with a reduced risk of cancer. The toxicity of vitamin A in doses exceeding those required for optimum nutrition, and the difficulty of epidemio- logical studies to distinguish the effects of carotenes from those of vitamin A, argue against increasing vitamin A intake by the use of supplements. VITAMIN C (ASCORBIC ACID) Epidemiological Evidence The associations of vitamin C with cancer in epidemiological stud- ies are mostly indirect since they are based on the consumption of foods known to contain high concentrations of the vitamin. In general, the data suggest that vitamin C may lower the risk of cancer, particu- larly in the esophagus and stomach. In 1964, Meinsma noted that the consumption of citrus fruits by cases of gastric cancer was lower than that by controls. Similar inverse associations between fresh fruit consumption or vitamin C intake and gastric cancer have been reported by Higginson (1966), Haenszel and Correa (1975), Bjelke (1978), and Kolonel et al. (1981~. These observations are consistent with the hypothesis that vitamin C protects against gastric cancer by blocking the reaction of secondary and higher amine s with nitrite to form nitrosamines (Correct et al., 1975). As noted in the discussion of vitamin A, Mettlin et al. (1981) found inverse associations of indices of both vitamin A and vitamin C consumption with esophageal cancer, based on frequency of consump- tion of selected food items by male cases and controls. The rela- tionship was stronger for vitamin C than for vitamin A, however, and only the association with vitamin C was statistically significant after controlling for smoking and alcohol use. In studies of human populations on the Caspian littoral of Iran, inverse associations have 9 - 7

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Vitamins 145 been found between esophageal cancer and consumption of fresh fruits and estimated intake of vitamin C, based on correlational and case- control data (Cook-Mozaffari, 1979; Cook-Mozaffari et al., 1979; Hormozdiari et al., 1975; Joint Iran-International Agency for Research on Cancer Study Group, 1977~. A protective role for vitamin C in laryngeal cancer was also inferred in a case-control study conducted by Graham et al. (1981~. These investigators found an inverse relationship between cancer risk and indices of both vitamins C and A, after controlling for cigarette smoking and alcohol consumption. There was a similar relationship for vegetable consumption in general, but not for cruciferous vegetables in particular. Wassertheil-Smoller et al. (1981) recently reported a similar inverse association between vitamin C consumption (calculated from analysis of 3-day records of foods and a 24-hour recall) and uterine cervical dysplasia in a case-control study of women in New York. The findings persisted after the investigators controlled for age and sexual activity in the analysis. In contrast, Jain _ al. (1980) found no association between vitamin C consumption and colon cancer in a case-control study based on quantitative data obtained from dietary histories. Experimental Evidence Vitamin C has also been studied for its effects on cancer under a variety of experimental conditions. The simplest studies are those that have demonstrated that ascorbic acid can prevent the reaction of nitrites with amines or amides to form carcinogenic nitroso compounds. Ascorbic acid effectively competes for the nitrite, thereby inhibiting the formation of the carcinogenic nitroso compounds (Ivankovic et al., 1975; Mirvish, 1981; Mirvish et al., 1972, 1975~. Investigations of this phenomenon In vitro and In viva have been published by a number of scientists. In a prototype in vitro study, Mirvish et al. (1972) demonstrated that ascorbic acid inhibited formation of n~troso com- pounds resulting from the reaction of nitrites with oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and dimethylamine. In subsequent _ viva studies, they showed that ascorbic acid inhibits formation of nitroso carcinogens in mice (Mirvish et al., 1975~. In their experimental model, Swiss and Strain A mice were fed amine s or amides in the diet and were given nitrite in their drinking water. Under these conditions, pulmonary tumors developed. The addition of ascorbic acid to the diet resulted in a marked inhibition of these tumors. Ascorbic acid also consistently produced an inhibitory effect in other _ viva studies when nitrite and amino compounds were admin- istered by the same routes (Ivankovic et al., 1975; Mirvish, 1981; Rustia, 1975~. The effect of vitamin C on carcinogenesis resulting from exposures to already formed carcinogens is not clearly understood. Experiments to study this are complicated by the fact that the guinea pig is

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146 DIET, NUTRITION, AND CANCER the only laboratory animal that, like primates, does not synthesize vitamin C. Moreover, the endogenous synthesis of vitamin C responds easily to various stimuli, e.g., exposures to certain xenobiotic compounds. Data presented in two abstracts indicate that ascorbic acid inhibited neoplasia of the large bowel in rats given 1,2-dimethylhydra- zine (Logue and Frommer, 1980; Reddy and Hirota, 1979~. Kallistratos and Fasake (1980) reported that administration of a high dose of ascorbic acid in the diet of rats inhibited the induction of sarcoma by benzo~a~pyrene. Only a few animals were used in this investigation. Soloway _ al. (1975) reported that ascorbic acid had no effect on the occurrence of neoplasia in the rat bladder after administration of FANFT. Overall, the reported protective effects of ascorbic acid on neoplasia are not impressive, except for those brought about through an indirect mechanism, i.e., the prevention of the formation of carcino- genic N-nitroso compounds. In only two instances have investigators reported inhibition of carcinogenesis in the same tissue, i.e., the large bowel (Logue and Frommer, 1980; Reddy and Hirota, 1979~. However, since these studies were reported only in abstract form, their results warrant further investigation. In a study with a small number of guinea pigs, a high dietary intake of ascorbic acid had a slight enhancing effect on the induction of sarcoma by 3 methylcholanthrene (Banic, 1981~. Russell et al. (1952) also studied the induction of sarcoma by the same compound in three groups of guinea pigs: a group deficient in vitamin C, a group receiving vitamin C but on a food-restricted diet, and a group fed ad libitum. The number of animals developing tumors was similar in all three groups, but the latent period was slightly shorter in the vita- min-C-deficient group, indicating that the response produced by vitamin C deficiency was very slight or nonexistent. Recently, observations on the effects of vitamin C on cells in culture have indicated that ascorbic acid can affect cellular mani- festations of malignancy. When C3H/lOTl/2 mouse embryo cells are exposed to 3-methylcholanthrene, morphological transformation occurs. However, the transformation is prevented if ascorbic acid is added to the culture medium. Addition of the ascorbic acid as late as 23 days after the treatment with 3 ~ethylcholanthrene still completely inhibits transformation. Under some circumstances, it is possible to cause reversion of chemically transformed cells to normal-appearing morpho- logica1 phenotypes by adding ascorbic acid to the culture medium (Benedict et al., 1980~. The mechanism for inhibition and reversion is presently unknown. The effects of ascorbic acid on human leukemia cells in culture have also been studied. Low concentrations of ascorbic acid were found to suppress growth of human leukemia cells from patients with acute nonlymphocytic leukemia under conditions in which growth of normal myeloid colonies was not suppressed (Park et al., 1980~. 9 - 9

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Vitamins 147 Summary Epidemiological Evidence. The epidemiological data pertaining to the effect of vitamin C on the occurrence of cancer are not extensive. Furthermore, they provide mostly indirect evidence since they are based on the consumption of foods, especially fresh fruits and vegetables, known to contain high concentrations of the vitamin, rather than on actual measurements of vitamin C intake. The results of several case- control studies and a few correlation studies suggest that the consump- tion of vitamin-C-containing foods is associated with a lower risk for certain cancers, particularly gastric and esophageal cancer. Experimental Evidence. In the laboratory, ascorbic acid can in- hibit the formation of carcinogenic _-nitroso compounds, both in vitro and in viva. On the other hand, studies of its inhibitory effect on - the action of preformed carcinogens have not provided conclusive results. In recent studies, the addition of ascorbic acid to cells grown in culture prevented the chemically induced transformation of these cells and, in some cases, caused reversion of transformed cells. Conclusion The limited evidence suggests that vitamin C can inhibit the formation of some carcinogens and that the consumption of vitamin-C- containing foods is associated with a lower risk of cancers of the stomach and esophagus. VITAMIN E (~-Tocopherol) Epidemiological Evidence There are as yet no epidemiological data associating vitamin E with cancer risk, and such data may prove difficult to obtain for several reasons. First, vitamin E is present in a wide variety of foods (e.g., vegetable oils, whole grain cereal products, and eggs), which makes it difficult to identify groups of people with substantially different levels of intake. In addition, a clear-cut deficiency has not been established in humans. Vitamin E is also relatively unstable during storage, and its concentration can vary greatly within individual foodstuffs. Experimental Evidence Of the various tocopherols, vitamin E (~-tocopherol) is most widely distributed among different foods and has the greatest biologi- cal activity (Harris et al., 1972~. The vast majority of studies of the relationship of the tocopherols and cancer have been conducted 9-10

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148 DIET, NUTRITION, AND CANCER with ~-tocopherol. Like vitamin C, a-tocopherol competes for availa- ble nitrite, thereby blocking the formation of carcinogenic nitroso compounds from reactions between nitrite and nitrosatable substrates such as amine s or amides (Fiddler et al., 1978; Mergens et al., 1978, 1979~. An important difference between these vitamins is their solu- bility. Ascorbic acid is water soluble, whereas a-tocopherol is sol- uble in lipids. Thus, the inhibitory effects of a-tocopherol would take place largely in a lipid milieu. There have been no in viva studies to determine the effects on neoplasia resulting from a-tocopherol-induced inhibition of nitroso compound formation. However, Kamm et al. (1977) have reported that the _ viva formation of nitrosamines from precursor compounds resulted in hepatotoxicity. In this study, rats were incubated with a solution containing sodium nitrite and aminopyrene. This was followed by oral administration of a-tocopherol or vehicle. Animals receiving the vehicle had elevated SGPT (serum glutamic-pyruvic transaminase), indi- cating liver damage. Rats receiving a-tocopherol had either a lower elevation of SGPT or no elevation at all, depending on the dose of a-tocopherol administered. These investigators also reported that the rats receiving a-tocopherol had a markedly lower level of nitrosamines in their serum than did the corresponding controls. Efforts to inhibit neoplasia by administering increased amounts of vitamin E have a long history. In one of the earliest studies, Jaffe (1946) reported that the number of mixed tumors resulting from intra- peritoneal injection of 3-methylcholanthrene was lower in rats re- ceiving a diet with added wheat germ oil than in rats on a control diet. Subsequently, Haber and Wissler (1962) studied the effect of a-tocopherol supplements on subcutaneous sarcomas induced by injecting mice with 3-methylcholanthrene. Their data suggested that ~-tocopherol inhibited the occurrence of these sarcomas. In studies by Epstein et al. (1967), ~-tocopherol and a number of other phenolic antioxidants did not suppress the formation of subcutaneous sarcomas induced in mice by injections of 3,4,9,10-dibenzpyrene. More recently, Wattenberg (1972) reported that addition of a-tocopherol to the diet prior to administration of the carcinogen failed to inhibit DMBA-induced neoplasia of the forestomach of mice. Several investigators have studied the effects of a-tocopherol on DMBA-induced formation of mammary tumors. Wattenberg (1972) reported that ingestion of high levels of ~-tocopherol only during the period before DMBA was administered did not inhibit the occurrence of mammary tumors. In a brief report, Harman (1969) presented data showing that a large vitamin E supplement in a semipurified diet fed from 11 days prior to DMBA administration until completion of the study decreased the number of tumor-bearing rats by slightly less than one-half. In another brief report, Lee and Chen (1979) indicated that rats fed diets either lacking ~-tocopherol or containing one-half the minimum level recommended had an increased tumor incidence as compared to animals receiving a diet with adequate or excessive amounts of vitamin E. 9-11

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Vitamins 151 The complex interrelationships between the B vitamins and other dietary components have been thoroughly examined in studies of diets deficient in lipotropes (e.g., methionine, choline, and folate) and high in fat content (Rogers and Newberne, 1980~. Although the major lipotropes are choline and methionine, folate (and to some extent vitamin B12) can also exert lipotropic action. Modulation of carcinogenesis by other vitamins, such as inositol and vitamin Be, may contribute to the overall lipotropic activity of these diets. Individual B vitamins may have enhancing effects on carcinogenesis, depending on experimental conditions. Thus, only carefully controlled experiments can shed light on the specific contribution of each of the B vitamins. The overall results clearly demonstrate that the effects of B vitamins on carcinogenesis depend on the specific chemical car- cinogen, the target organ, and the strain and sex of the animal. The relative importance of the individual dietary components may vary, depending on experimental conditions. The relationship of the results of the short-term tests to those from in viva studies for carcinogenicity of chemicals in animals adds a further complication. These differences in the findings from these two types of studies have been reviewed for various compounds includ- ing aflatoxin B1 (Rogers and Newberne, 1969), N-nitrosodiethylamine (Rogers, 1977), N-nitrosodibutylamine, N-nitrosodimethylamine, N-2- fluorenylacetamide, 7,12-dimethylbenzanthracene, 1,2-dimethylhydra- zine, and 3,3-diphenyl-3-dimethylcarbamyl-1-propine (Rogers and Newberne, 1980~. Rogers and Newberne (1980) observed that the most consistent results obtained with lipotrope-deficient diets in rats were enhancement of hepatocarcinogenesis and, to a lesser extent, of colon carcinogenesis. These diets do not have a consistent effect on tumor induction in target organs other than the liver and colon (Rogers, 1977~. In many cases, abnormalities in the metabolism of carcinogens can be demonstrated; however, their effects on tumor incidence cannot always be predicted. Recently, considerable effort has been expended to determine whether or not the metabolism and transport of vitamins or the binding of the appropriate coenzyme forms to apoenzymes are altered in tumor cells (Thanassi et al., 1981; Tryfiates, 1981~. For instance, in Morris hepatoma cells, the transport and phosphorylation of pyridoxine appear to be severely impaired (Thanassi et al., 1981~. Effects on the metabolism of riboflavin have also been reported (Rivlin, 1973), but it is not known whether the observed alterations have any influence on the modulation of carcinogenesis. The alterations in vitamin B6 metabolism may be due to secondary changes in the metabolism of amino acids, especially tryptophan (Bell, 1980; Bell et al., 1972; Byar and Blackard, 1977~. The effects on carcinogenesis by the B vitamins cannot be ascribed solely to effects modulating the stages of initiation or promotion 9-14

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152 DIET, NUTRITION, AND CANCER (Pitot and Sirica, 1980~. These vitamins may also modulate other processes such as immunosurveillance, which may affect the ultimate outcome of carcinogenesis. Impairment of the immune function has been demonstrated in pyridoxine-deficient animals (Axelrod and Trakatellis, 1964), and it seems likely that major disruption of energy or carbohy- drate metabolism by deficiencies of riboflavin or thiamine, as well as disruption of normal cell replication by deficiencies in folate or vitamin B12' would affect immune surveillance. Because of the inter- relationships among the B vitamins and their relationships with other major dietary components, it is difficult to explain specifically the effects on promotional events (Diamond et al., 1980). The modulation of carcinogenesis by the B vitamins under conditions of normal dietary intake is probably minimal. However, a change of in- take of a specific B vitamin may be warranted when a specific chemical carcinogen is present. Summary and Conclusions l The relationship of dietary B vitamins to the occurrence of cancer has not been studied epidemiologically. There have been a few inade- quate laboratory investigations to determine whether there is a rela- tionship between the various B vitamins and the occurrence of cancer. Therefore, no conclusions can be drawn. 9-15

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