Dietary control of cancer.

Many laboratory studies and human epidemiological data suggest that most cancer deaths are attributable to lifestyle, including nutritional factors and tobacco and alcohol consumption. Tobacco consumption is causally related to cancer of the lung, mouth, larynx, esophagus, bladder, kidney, and pancreas. Nutrients and non-nutrient dietary components probably account for cancer of the colon, breast, prostate, and stomach. This report is based on literature and our own data pertaining to the role of dietary fat, calories, and fiber in the development of colon and breast cancer. We also discuss the evidence from epidemiological, mechanistic, and preclinical efficacy studies indicating a protective effect of micronutrients, non-nutrients, and certain antioxidants in food against oral and lung cancers. Given the continuing cancer burden and the relatively slow impact of proven cancer treatment strategies in reducing cancer mortality, it is essential to evaluate promising nutrients and non-nutrients in foods as chemopreventive agents in persons at increased risk for cancer. Development of reliable intermediate biomarkers is valuable for clinical chemoprevention intervention trials. The purpose of this report is to provide the reader with plausible approaches to cancer control.

Effects of dietary fat content on the metabolism of NNK and on DNA methylation induced by NNK.

The available data support the concept that high-fat diets increase cytochrome P-450 activities in the liver, leading to increased rates of carcinogen metabolism and, in some instances, DNA adduct formation. Therefore we investigated whether a high-fat diet can also influence DNA methylation by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of rats. Male F344 rats were fed a regular AIN-76A low-fat (5% corn oil) or AIN-76A high-fat (23.5% corn oil) diet. After three weeks on this dietary regimen, the animals were injected subcutaneously once daily for four days with NNK at 0.39 mmol/kg body wt. Groups of rats were sacrificed 4 and 24 hours after the last NNK administration; livers and lungs were excised for DNA isolation. We found that the high-fat diet significantly enhanced the formation of O6-methylguanine (O6-mGua) in the rat lung four hours (p < 0.01) after the last carcinogen administration. This may, in part, account for our previous finding in regard to the enhancing effect of the high-fat diet on NNK-induced lung carcinogenesis. There was no effect on O6-mGua or 7-mGua in the rat liver at either time point. To further elucidate the enhancing effect of the high-fat diet on DNA methylation by NNK in the lung, we determined its effect on the in vitro and in vivo metabolism of NNK. The in vitro data indicated that dietary fat has no measurable effect on liver and lung microsomal mixed-function oxidase in catalyzing the metabolic activation of NNK. The results of the metabolism study of NNK in vivo appear to be consistent with the in vitro finding, in that fat had no effect on the excretion pattern of NNK or on the distribution pattern of its urinary metabolites. It is apparent that the enhancing effect of the high-fat diet on O6-mGua in the lung of rats that was measured four hours after NNK injection requires future investigations.

Nutrition and prostate cancer: a proposal for dietary intervention.

In this review, we consider the evidence from geographic and metabolic epidemiology and laboratory studies with human prostate cancer cell lines and animal models that emphasizes the need for the development and implementation of a dietary intervention trial in prostate cancer patients. It is concluded that such a trial should include a reduction in total fat consumption to 15% of total calories and supplementation of the diet with selenium, vitamin E, and a soya product. The low-fat intervention would provide an appropriate reduction in the intake of any specifically targeted dietary fatty acid, such as linoleic acid or alpha-linolenic acid.

Adherence to a dietary fat intake reduction program in postmenopausal women receiving therapy for early breast cancer. The Women's Intervention Nutrition Study.

PURPOSE: To evaluate the feasibility of integrating a program based on dietary fat intake reduction into adjuvant treatment strategies for postmenopausal women receiving therapy for early breast cancer. PATIENTS AND METHODS: Two hundred ninety postmenopausal women with localized (stage I to IIIa) breast cancer receiving conventional systemic therapy provided informed consent and were randomized in a multicenter trial to either a dietary intervention group receiving a program of individualized instruction for reducing total fat intake or a dietary control group with minimal dietary counseling. RESULTS: Significantly reduced (P < .001) fat intake (in terms of percent calories derived from fat) was observed in the intervention group versus the control group at 3 months (20.3% +/- 2.4% v 31.5% +/- 2.6%, mean +/- SD, respectively) and maintained throughout 24 months of observation. The 50% reduction in daily fat-gram intake (from 66 +/- 23 to 33 +/- 14 g, P < .001) seen at 6 months was associated with reduced saturated fat, monounsaturated fat, polyunsaturated fat, and linoleic acid (P < .001). Significantly lower body weight was also seen in intervention compared with control patients at all observation periods, resulting in a 3.3-kg weight difference 18 months after randomization (P < .001). CONCLUSION: Substantial and sustained dietary fat reduction with associated weight change can be achieved at relatively low cost within the context of conventional multimodality clinical management of postmenopausal women with localized breast cancer. This result supports the feasibility of conducting a full-scale evaluation of the influence of dietary fat intake reduction on the clinical outcome of breast cancer patients.

A study of tobacco carcinogenesis: effect of the fat content of the diet on the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.

3 Epidemiological studies indicate that the risk of cigarette smokers for cancer of the lung and of the pancreas is influenced by the fat content of the daily diet. In a long-term bioassay (24 months), we gave F344 rats 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific and strongly carcinogenic N-nitrosamine, as a 2 ppm solution in the drinking water. One group of rats was given a high-corn oil diet (23.5%), and the second group received a low-corn oil diet (5.0%). The animals on the high-corn oil diet and NNK (NNK-HF), and the control animals on the same diet but on tap water (HF) had significantly higher body weights and shorter life spans than the rats on a low-corn oil diet and NNK (NNK-LF) and the corresponding control rats receiving the low-corn oil diet and tap water (LF). Eighteen months into the bioassay, 16 of 60 rats in the NNK-HF group had developed lung tumors averaging 6.8 mm2, while 3 of 60 rats in the NNK-LF group had tumors averaging 2.5 mm2. At the termination of the experiment after 24 months, the numbers of rats with lung tumors in the NNK-HF and NNK-LF groups did not significantly differ from each other, nor was there a difference in the size of the lung tumors. The effect of dietary fat on the pancreas tumor incidence was more pronounced. After 18 months, 11 of 60 rats treated with NNK-HF but only one of 60 rats treated with NNK-LF had developed pancreas tumors. At the termination of the study, 28 NNK-HF-treated rats had pancreas tumors (17.5 +/- 13.5 mm) compared to 19 NNK-LF-treated rats (9.6 +/- 11.7 mm2). After 24 months 6 of 20 rats in each of the control groups (HF and LF) had developed pancreas tumors. In fact, there was an increasing trend of development of pancreas tumors in these control rats with aging regardless of dietary fat variance. However, in view of the observed tumor acceleration and enhancement this study points to the importance of evaluating both exposure to tobacco carcinogens and dietary fat intake as risk factors for tobacco users.

Vitamin supplement use in a hospital-based population.

Vitamin supplement histories were taken from a sample of approximately 3,600 individuals (2,461 men and 1,181 women) from a hospital-based population. Multivitamin preparations were the most commonly used vitamin supplements (32% of men, 37% of women) followed by vitamins C (men 11%; women 16%) and E (men 17%; women 23%). The most common combination of supplements among the multi-users was vitamins C and E. Vitamin supplement use was positively associated with education in both sexes. Among women, there was a negative association between vitamin supplement consumption and Quetelet Index. No association was found between vitamin use and smoking status or alcohol use or amount of alcohol consumed.

Vitamin supplement use and risk for oral and esophageal cancer.

In a hospital-based case-control study, 290 oral cancer cases and 133 esophageal cancer cases were queried as to smoking status, alcohol consumption, and dietary exposures, including vitamin supplement history. Among oral cancer cases, vitamin E use appeared to exert a protective effect. Vitamins C and E had protective effects among esophageal cancer cases. When stratified by smoking status, the protective effect of vitamin C use in esophageal cancer was significant only among current smokers, as was vitamin B use. A reduced risk of oral cancer was correlated with multivitamin use and increasing vegetable consumption, as was vegetable/fruit consumption and vitamin C supplementation. Among esophageal cancer cases, increasing meat consumption and vitamin C use were associated with a significantly reduced cancer risk.

Dietary habits of smokers, people who never smoked, and exsmokers.

A large database on hospital patients with illnesses not related to tobacco or alcohol was used to investigate the dietary habits of males and females who never smoked, who were exsmokers, and who currently smoked. Smoking was positively related to meat consumption and negatively related to cereal consumption in males. Both male and female smokers consumed fewer vegetables and fruits but more alcohol and coffee than did people who never smoked. Exsmokers' diets were similar to those of people who never smoked. These results emphasize the importance of ruling out potential confounders or effect modifiers when studying the role of meat, milk, fruits, vegetables, cereal, coffee, or alcohol intake in the etiology of tobacco-related diseases.

Reproducibility of food frequency measurements and inferences from a case-control study.

To investigate the relationship between the reproducibility of measurements of exposure from a frequency questionnaire and inferences from a case-control study, 229 patients were reinterviewed on the telephone an average of 6 weeks after the original interview. Several indices of agreement were computed. Information on smoking and use of alcohol and coffee was quite reproducible, as reflected by most measures of agreement, using grouped or continuous data. Frequency of meat, vegetable, and fruit intake had low reproducibility. For all variables, reproducibility was similar for cases and controls. Reproducibility of the exposure variables was a good predictor of the reproducibility of the relative odds (RO) obtained with the first and the repeat interviews. Lack of reliability of the exposure variable appeared to produce fluctuations in the ROs in either direction, even though the same degree of agreement was observed for cases and controls. This situation may partially explain discrepant findings between case-control studies of diet and chronic diseases.

Do dietary monounsaturated fatty acids play a protective role in carcinogenesis and cardiovascular disease?

Evidence gleaned from epidemiology, nutritional anthropology, and laboratory animal studies is cited to support the hypothesis that the metabolism of 20th century man is poorly adapted to the present day high-fat, high-saturated fat Western diet, and that the emergence of heart disease and cancer as the major killing diseases in modern industrial societies may have resulted, at least in part, from the inability of our ancient metabolic heritage, adapted over eons to a low-fat, high-monounsaturated fat diet, to cope with our modern Western diet--a diet of unusually high caloric density that appeared only recently (approximately 250 years ago) in the 100,000+ year evolutionary history of Homo sapiens.

International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption.

The 1978-1979 mortality rates for cancers of the breast, prostate, ovary, and colon in 26 to 30 countries were related to the average 1979-1981 food availability data published by the United Nations. The previously described relationship between breast cancer mortality rates and animal fat consumption continues to be evident, and applies also to the other three tumor types. The correlation with breast cancer was particularly strong in postmenopausal women. Since 1964, particularly notable increases in both breast cancer mortality rate and dietary fat intake have occurred in those countries with a relatively low breast cancer risk. The international comparisons support evidence from animal experiments that diets in which olive oil is a major source of fat are associated with reduced breast cancer risk. The excess in mortality rates for breast and ovarian cancer in Israel relative to the national animal fat consumption may be due to the mixed ethnic origin of the Israeli population. Positive correlations between foods and cancer mortality rates were particularly strong in the case of meats and milk for breast cancer, milk for prostate and ovarian cancer, and meats for colon cancer. All four tumor types showed a negative correlation with cereal intake, which was particularly strong in the case of prostate and ovarian cancer. Although, in general, there was a good positive correlation between prostate and breast cancer mortality rates and between prostate cancer and animal fat, discrepancies in national ranking indicate the operation of other etiologic factors that modify risk. The observed positive correlations between the four cancer mortality rates and caloric intake from animal sources, but negative correlations for vegetable-derived calories, suggest that, of the two, animal fat and not energy is the major dietary influence on cancer risk.

Case-control study of decaffeinated coffee consumption and pancreatic cancer.

The relationship between decaffeinated coffee consumption and pancreatic cancer was examined using data from a hospital-based case-control study of individuals aged 20-80 years in 18 hospitals in 6 United States cities, from January 1981 to December 1984. Among the males, 127 cases and 371 controls were examined, while for females, the figures were 111 and 325 for cases and controls, respectively. Decaffeinated coffee use was not associated with an increased risk of pancreatic cancer in males (odds ratio = 0.7 for 3 or more cups/day; 95% confidence interval = 0.4-1.4). For females, an elevated risk was seen for drinkers of 1-2 cups/day (odds ratio = 1.6; 95% confidence interval = 1.0-2.7), but this finding was of borderline significance and elevation in risk was not found for drinkers of 3 or more cups/day (odds ratio = 0.9; 95% confidence interval = 0.4-1.9). Cigarette smoking was significantly associated with pancreatic cancer in both males and females. Factors examined and not found to be related to pancreatic cancer included education, occupation, religion, marital status, alcohol drinking, saccharin use, height, weight 5 years before hospitalization, history of previous diseases, and residence.

Bladder cancer in nonsmokers.

Potential risk factors for bladder cancer were studied in a series of 76 male and 76 female bladder cancer cases and 238 male and 254 female controls who reported never having smoked. Risk factors included usual occupation, smoking by the spouse, sidestream smoke exposure at home and at work and in transportation, coffee drinking (caffeinated and decaffeinated), artificial sweetener use, body mass index, and a history of diabetes and high blood pressure. No association was found with spouse's smoking or reported sidestream smoke exposure, coffee drinking, artificial sweetener use, or a number of other variables; however, there was some indication that several occupations were overrepresented in the cases. A positive association was found with snuff use in women, but the numbers were small (three cases and one control). Restriction of the study to lifetime nonsmokers permitted the assessment of potential risk factors in the absence of potential confounding and interactive effects of smoking. The study had adequate statistical power to detect moderately small elevated risks due to the main factors examined.

Epidemiology of coffee and pancreatic cancer.

The association between pancreatic cancer and putative risk factors was examined using 275 incident cases and 7994 controls interviewed in six United States cities for a major study of tobacco-related diseases. From the comparison population were excluded patients with other diseases postulated to be associated with pancreatic cancer (e.g., other pancreatic diseases and diseases of the gallbladder) and those admitted for disorders known to be associated with smoking. After carefully controlling for age, the data failed to indicate an association between coffee consumption and pancreatic cancer (odds ratio congruent to 1.0). This was true both before and after adjustment for cigarette smoking and in both males and females. There was a statistically significant association between pancreatic cancer and smoking in both males and females (odds ratio 3.0 for males who smoked more than 1.5 packs/day and 2.0 for females who smoked more than 1 pack/day).

Effect of diet on plasma and urinary hormones in South African black men with prostatic cancer.

Epidemiological evidence suggests that the incidence and death rate from prostatic cancer, an endocrine-associated disease, are related to environmental factors including diet. In this study, a comparison of serum and urinary levels of steroid hormones was carried out in healthy elderly rural vegetarian South African black men, a low-risk population, and a comparable group of men with prostatic cancer. In these prostatic cancer patients, plasma androgen levels decreased, while estrogen levels increased. Concomitantly, the androsterone:etiocholanolone ratio increased, and a greater proportion of estrogens was excreted as estriol. When transferred to a Western diet, plasma androgens showed a further decrease and a greater increase in estrone in prostatic cancer patients. In prostatic cancer patients, the total urinary androgen and estrogen levels were unaltered. However, in elderly healthy men, the Western diet decreased the excretion of estrogens and androgens. Thus, a Western diet supplemented the decrease in plasma androgens initially present in these patients. Evidence suggests that the decrease in plasma androgens increases the estrogen: androgen ratio, which may lead to hyperplasia of the prostatic ductal epithelia, a change enhanced by a Western diet. Changes in urinary steroid hormone levels in South African black patients comparable to those reported in white prostatic cancer patients indicate that hormonal changes must be related to several environmental factors, apart from diet. A simultaneous study of the steroid hormone composition of blood and prostatic fluid in this low-risk population is suggested.

The epidemiology of bladder cancer: a second look.

A case-control study among 574 male and 158 female bladder cancer patients and equal numbers of matched controls was conducted between 1969 and 1974 in 17 hospitals in six United States cities. We determined that cigarette smokers of both sexes were at higher relative risk than nonsmokers. Cigarette smoking was responsible for about one-half of male and one-third of female bladder cancer. There was an excess of bladder cancer patients with some previous occupational exposure, such as rubber, chemicals, and textiles. A weak association with coffee drinking, which appeared to be independent of smoking, was found for males. Users of artificial sweeteners were not over-represented among the cases. The authors conclude that the epidemiologic pattern of bladder cancer cannot be fully accounted for by cigarette smoking and occupational exposure and suggest a series of metabolic studies to assess the role of additional factors, such as nutrition.