Leonard A. Cohen

Nutrition and its Relationship to Cancer

Publisher Summary Nutrition is related to the development of cancer in three ways: (1) food additives or contaminants may act as carcinogens, cocarcinogens, or both; (2) nutrient deficiencies may lead to biochemical alterations that promote neoplastic processes; and (3) changes in the intake of selected macronutrients may produce metabolic and biochemical abnormalities, either directly or indirectly, which increase the risk for cancer. Specific carcinogens play a minor role as initiators in the relationship between nutrition and the development of cancer. This chapter covers six types of cancer: large bowel cancer, colon carcinogenesis, stomach cancer, cancer of the upper alimentary and respiratory tract, cancer of the pancreas, and breast cancer. In four of these—breast, large bowel, stomach, and head and neck—the epidemiologic evidence is overwhelming that nutritional factors have a major etiological role. Dietary factors are also implicated in the etiologies of the two remaining types of cancer—pancreas and prostate—but the epidemiologic evidence is not overwhelming. The chapter also presents an evaluation of the status of the relationship between nutrition and cancer in man, discusses the use of animal models to determine if the etiological factors established for man can be modified in an experimental setting, and makes recommendations for additional research and possible preventive measures.

A Review of Animal Model Studies of Tomato Carotenoids, Lycopene, and Cancer Chemoprevention

There are relatively few reports on the cancer chemopreventive effects of lycopene or tomato carotenoids in animal models. The majority, but not all, of these studies indicate a protective effect. Inhibitory effects were reported in two studies using aberrant crypt foci, an intermediate lesion leading to colon cancer, as an end point and in two mammary tumor studies, one using the dimethylbenz(a)anthracene model, and the other the spontaneous mouse model. Inhibitory effects were also reported in mouse lung and rat hepatocarcinoma and bladder cancer models. However, a report from the authors laboratory found no effect in the N-nitrosomethylurea-induced mammary tumor model when crystalline lycopene or a lycopene-rich tomato carotenoid oleoresin was administered in the diet. Unfortunately, because of differences in routes of administration (gavage, intraperitoneal injection, intra-rectal instillation, drinking water, and diet supplementation), species and strain differences, form of lycopene (pure crystalline, beadlet, mixed carotenoid suspension), varying diets (grain-based, casein based) and dose ranges (0.5–500 ppm), no two studies are comparable. It is clear that the majority of Ingested lycopene is excreted in the feces and that 1000-fold more lycopene is absorbed and stored in the liver than accumulates in other target organs. Nonetheless, physiologically significant (nanogram) levels of lycopene are assimilated by key organs such as breast, prostate, lung, and colon, and there is a rough dose-response relationship between lycopene intake and blood levels. Pure lycopene was absorbed less efficiently than the lycopene-rich tomato carotenoid oleoresin and blood levels of lycopene in rats fed a grain-based diet were consistently lower than those in rats fed lycopene in a casein-based diet. The latter suggests that the matrix in which lycopene is incorporated is an important determinant of lycopene uptake. A number of issues remain to be resolved before any definitive conclusions can be drawn concerning the anticancer effects of lycopene. These include the following: the optimal dose and form of lycopene, interactions among lycopene and other carotenoids and fat soluble vitamins such as vitamin E and D, the role of dietary fat in regulating lycopene uptake and disposition, organ and tissue specificity, and the problem of extrapolation from rodent models to human populations.

Diet and breast cancer in causation and therapy

The major macronutrient associated with increased breast cancer risk is dietary fat. Evidence for this association is based on epidemiologic, clinical, and laboratory animal studies. In addition, there is suggestive epidemiologic evidence that differences in postmastectomy survival rates in Japan and the United States may be attributable to differences in dietary fat intake. The importance of the type of fat consumed, as well as its amount, has emerged as an issue of major importance. Some oils, including those rich in monounsaturates, medium chain fatty acids, or omega‐3 (n‐3) fatty acids appear to lack tumor‐promoting effects despite their presence in the diet at high levels. Possible mechanisms by which dietary fat may exert its effects could be either direct or indirect. Direct mechanisms involve dietary modification of membrane structure and function; indirect mechanisms involve alterations in the endocrine system, and/ or the metabolism of essential fatty acids to biologically active eicosanoids such as prostaglandins, and suppression of immune responses. Dietary guidelines and dietary intervention trials for the primary and secondary prevention of breast cancer are discussed.

Effect of varying proportions of dietary menhaden and corn oil on experimental rat mammary tumor promotion.

Dose-related effects of long-chain highly unsaturated n−3 fatty acids on the development ofN-nitrosomethylurea (NMU)-induced rat mammary tumors were assessed in female F344 rats. Four test groups (36 rats/group) were fed the following high-fat (HF) diets (23% fat, w/w): Group 1, 18% menhaden oil (MO) and 5% corn oil (CO); Group 2, 11% MO and 11.8% CO; Group 3,5% MO and 18% CO; Group 4, CO alone. A fifth group, serving as an internal control, was fed a low-fat diet containing 5% CO alone. Experimental diets were begun after initiation with NMU, and the experiment was terminated 31 wk later. Total tumor numbers in the five groups were 28, 16, 32, 26 and 11, respectively, indicating that the promotion phase of NMU-induced carcinogenesis was significantly suppressed only when equal parts of CO and MO (Group 2) were fed or when CO alone was fed at 5% (w/w). At high (Group 1) or low (Group 3) levels of MO, tumor numbers were indistinguishable from the HF CO group (Group 4). The same pattern was observed when assessed in terms of cumulative tumor incidence and multiplicity. However, when expressed in terms of final tumor incidence, dietary MO did not suppress tumor promotion in a statistically significant fashion at any concentration. Animals fed MO gained weight at the same rate as those fed CO, indicating that the presence of MO in the diet did not result in food avoidance behavior. Measurement of total serum cholesterol indicated an inverse trend with respect to the MO content of the diet. Analysis of serum fatty acid profiles indicated that the proportion of n−3 and n−6 polyun-saturated fatty acids (PUFA) in the serum reflected that of the diet. These results support the hypothesis that the relative proportions of dietary n−3/n−6 fatty acids play an important role in the suppression of experimental mammary tumorigenesis and suggest that changes in circulating cholesterol or n−3 PUFA levels, induced by dietary MO, are not directly related to tumor development.

High Dietary Fat, Elevation of Rat Serum Prolactin and Mammary Cancer

In a previous communication (1) we reported that 7,12-dimethylbenz (a) anthracene (DMBA)-treated rats fed a 20% fat semisynthetic diet exhibited a higher mean mammary tumor incidence (56%) than rats fed a 0.5% fat diet (34%), thus confirming the earlier studies of Carroll and coworkers (2, 3). Also, on the basis of experiments using hormone antagonists we tentatively concluded that the high fat effect was mediated through elevated serum prolactin and that changes in the estrogen-receptor system were probably not involved. We now submit direct evidence, based on the radioimmunoassay of serum prolactin, that animals maintained on high-fat diets (HF) exhibit significantly higher serum prolactin levels during the proestrus-estrus period than animals fed low fat diets (LF). Materials and Methods. Forty virgin female Sprague-Dawley rats (ARS/Sprague-Dawley, Madison, WI) were housed five in a cage in a temperature (24° ± 1°), humidity (50%) and light controlled (12 hr/ day) room and fed Purina Lab Chow and water ad libitum. When 50 days old, the rats were separated into two groups of 20 each and fed a high (20%) lard semisynthetic diet, as described previously (1), or a low (0.5 %) lard diet. After 2 and 5 mo on the diets, tail blood was taken once a week for 3 wk and the serum separated and stored at —20°. Bleeding was carried out under ether anesthesia at 4:00 pm and completed within 2 min. Also, during these 3 wk, vaginal smears were taken daily at 4:30 pm to determine the estrous stage. Radioimmunoassay of serum prolactin from cycling rats was carried out using reagents and methods supplied by the Hormone Distribution Program, National Institutes of Arthritis, Metabolic and Digestive Diseases, Bethesda, MD. Rat prolactin was iodinated with 125I obtained from Cambridge Nuclear Corp., Billerica, MA.

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.

A rationale for dietary intervention in postmenopausal breast cancer patients: An update

In 1982, we proposed a large-scale randomized prospective trial to test the hypothesis that decreasing dietary fat intake from 38% to 20% of total calories would increase the disease-free interval and/or five-year survival rate for postmenopausal breast cancer patients. We now review new evidence from epidemiological studies, laboratory animal model studies, and preliminary feasibility trials that has accumulated over the past decade, in support of such a trial, and suggest that a more appropriate dietary goal is a reduction in fat intake to 15% of total calories.

Protective Mechanisms of Dietary Fibers in Nutritional Carcinogenesis

Fibers in foods are complex carbohydrates. There are several types of fiber, but, for the purpose of mechanistic insight into their mode of protective action in carcinogenesis, classification into two broad types, soluble and insoluble fibers, is warranted. Soluble fibers are present in fruits, vegetables, and certain grains like oats. This type of fiber undergoes metabolism in the small intestine and especially in the large intestine through bacterial enzymes, converting it to products that increase stool size only moderately. But, they have appreciable effects in modifying the metabolism of colon carcinogens like azoxymethane to yield detoxified products and, thus, reducing colon carcinogenesis. In contrast, insoluble fibers present in sizeable amounts in bran cereals, like wheat or rice, are not significantly metabolized by enzymes in the intestinal flora. Such fibers increase stool size substantially through several mechanisms, including higher water retention. The larger bulk dilutes carcinogens, especially tumor promoters such as secondary bile acids, resulting in lower risk of colon cancer in animals and in humans. Evidence in animal models and in humans also indicates that fiber may lower the risk of breast cancer, possibly via an endocrine mechanism. Based on these concepts, increased intake of total fiber, but especially of wheat bran cereal fiber, to yield a daily stool in adults of about 200 grams can significantly reduce the risk of colon cancer and, to a lesser but definite extent, of breast cancer. Thus, adequate fiber intake from cereals, fruits, and vegetables can help prevent important types of human cancer.

Diet and endocrine-related cancer.

In women, dietary modification and life style affect the risk of breast cancer and may alter the hormonal status, while in experimental animals diet can alter the incidence of induced mammary tumors. In this study, a high fat diet increased the incidence of DMBA‐induced tumors in rats while this increase in incidence was lowered and the effect of a high fat diet obliterated by an anti‐prolactin during CB154. Premenopausal Japanese women had a higher estradiol level than their Caucasian counterpart. In Japanese but not Caucasian breast cancer patients, the estradiol decreased. When nurses were transferred from the Western to a vegetarian diet, the menstrual cycle was shortened, while their prolactin and testosterone decreased. Data indicate that dietary factors influence tumor incidence and hormone profile in rat mammary cancer and the hormonal status in women.

A rationale for dietary intervention in the treatment of postmenopausal breast cancer patients

Abstract A rationale is given for the use of a low‐fat diet as a form of adjuvant therapy for postmenopausal breast cancer patients. The rationale is based on both epidemiological and experimental evidence, accrued over the past 40 years, suggesting that dietary fat is an important determinant of both breast cancer risk and probability of survival after surgery. A randomized prospective clinical trial would provide the most direct and feasible experimental mechanism for testing the hypothesis that decreasing the consumption of dietary fat will increase the disease‐free interval and/or the 5‐year survival rates of postmenopausal breast cancer patients.