Dietary calcium and vitamin D modulate 1,2-dimethylhydrazine-induced colonic carcinogenesis in the rat

To determine whether supplemental dietary calcium and/or vitamin D deficiency are involved in modulating colon cancer induced by 1,2-dimethylhydrazine (DMH), Sprague-Dawley rats were fed diets containing either: (a) a normal content of calcium (0.87%) and phosphorus (0.60%) with 2.2 IU of vitamin D3 per g of feed (group A); (b) the same diet as group A, but with calcium and phosphorus increased to 1.80 and 0.80%, respectively (group B); or (c) a vitamin D-deficient diet with supplemental calcium (1.80%) and phosphorus (0.80%) (group C). After 6 weeks on their respective diets, one-half the animals in each group were given s.c. injections of either vehicle or DMH (20 mg/kg body weight/week) for 26 weeks. Animals were then sacrificed and the incidence of tumors as well as the number of tumors per tumor-bearing rat were determined. Colonic mucosal polyamine levels were measured after 15 weeks of exposure to vehicle or DMH, before development of histologically recognizable neoplasms. The results of these experiments demonstrated that neither calcium supplementation alone nor supplemental calcium in conjunction with vitamin D deficiency altered the incidence of colonic cancer induced by this carcinogen. Supplemental calcium, however, significantly decreased the number of rats with multiple tumors and reduced tumor size. Moreover, vitamin D deficiency abolished these protective effects of calcium on colon cancer in this experimental model. DMH treatment increased polyamine levels in the premalignant colonic mucosa in group A rats. This carcinogen-induced effect was blunted by high dietary calcium. Vitamin D-deficient, calcium-supplemented rats (group C) showed an increase in N1-acetylspermidine, but not the other polyamines, with DMH treatment.     

Effect of moderate vitamin A supplementation and lack of dietary vitamin A on the development of mammary tumors in female rats treated with low carcinogenic dose levels of 7,12-dimethylbenz(a)anthracene

We examined the effect of moderately increased and of marginal continued dietary supplementation of vitamin A (retinyl acetate) and the effect of lack of dietary vitamin A on the initiation and promotion stages of mammary tumorigenesis in female Sprague-Dawley rats treated with a single low (0.5 mg/100 g body weight) or very low (0.1 mg/100 g body weight) dose of i.v.-administered 7,12-dimethylbenz(a)anthracene. The number of mammary tumors was significantly (P less than 0.05) reduced if prior to and during initiation with 7,12-dimethylbenz(a)anthracene the rats were fed a moderately increased (30 micrograms/day) or marginal (3 micrograms/day) amount of vitamin A, compared to rats fed an adequate (10 micrograms/day) amount of vitamin A. The number of mammary tumors was also significantly (P less than 0.05) reduced when a moderately increased or marginal amount of vitamin A was provided during the tumor promotion phase. In addition, the number of mammary tumors was significantly (P less than 0.05) reduced by the lack of dietary vitamin A during both the initiation and promotion stages of this tumorigenic process, when compared to vitamin A adequate, ad libitum-fed rats, but not when compared to vitamin A adequate, food-restricted controls. The reduction in numbers of mammary tumors observed in these studies was reflected primarily in significant (P less than 0.05) decreases in mammary fibroadenomas; the number of mammary carcinomas was often reduced, but due to a low frequency of the carcinomatous lesions, this reduction did not reach the 5% level of statistical probability. Plasma and liver vitamin A levels were determined during both the initiation and promotion stages. As the dietary supplementation of vitamin A increased from 0 to 30 micrograms/day, there was an increase in mean liver and plasma vitamin A levels. No consistent correlation between plasma and liver vitamin A levels and the occurrence of mammary tumors was observed, except with the moderately increased (30 micrograms/day) intake of vitamin A, that resulted in a small, but statistically significant (P less than 0.05) increase of serum retinol at initiation; this may account for the observed reduction in mammary tumors. These results provide evidence that moderate alterations in vitamin A consumption can modulate low-dose chemically induced mammary gland tumorigenesis. Most importantly, suppression of mammary gland tumorigenesis can be achieved by moderately increased, frequent, and regular consumption of vitamin A; prolonged consumption of vitamin A-deficient diets or diets marginal in vitamin A does not enhance the risk of mammary tumor development.     

Interaction of dietary fat and protein on pancreatic carcinogenesis in Syrian golden hamsters

The role of interactions between dietary fat and protein in experimental pancreatic cancer was determined in Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two levels of corn oil [4.5 and 18 g/385 kilocalorie (kcal)] were fed with each of two levels of casein (9 g/385 kcal and 36 g/385 kcal), either before or after a single sc injection of BOP (10 mg/kg body wt) at 8 weeks of age. Control diet was fed at other times (9 g corn oil and 18 g casein/385 kcal). The pancreatic ductular carcinoma incidence and multiplicity (average No. of tumors/tumor-bearing animals) increased as dietary fat and protein levels rose in hamsters fed the four diets after carcinogen treatment. Enhanced carcinogenesis by high-fat (HF) diets occurred only in hamsters fed the high-protein (HP) level, and protein effects were seen only with the HF diets. The low-fat-low-protein (LF-LP) diet inhibited pancreatic carcinogenesis among the hamsters given the four diets before BOP treatment. Pancreatic adenoma yields were elevated in hamsters given either HF or HP diets following BOP treatment, by comparison with the low levels. However, when diets were fed before BOP treatment, an increased yield occurred with the rise in protein, but the yield was reduced in males with the increase in fat. Acinar cell nodules were observed primarily in hamsters fed LP levels after BOP, and their multiplicity was highest in those given the HF diet. The interaction between dietary fat and protein demonstrated the interdependence of the effects of these two nutrients on pancreatic carcinogenesis in hamsters.     

Influence of dietary fat on the induction of mammary tumors by N-nitrosomethylurea: associated hormone changes and differences between Sprague-Dawley and F344 rats

A single iv dose of N-nitrosomethylurea (NMU, 50 mg/kg) given to 50-day-old F344 and Sprague-Dawley rats was sufficient to induce mammary adenocarcinomas. The Sprague-Dawley rats were more sensitive to the carcinogenic action of NMU than were the F344 rats. Moreover, regardless of strain, tumors developed in greater numbers and with a shorter latent period in animals fed a high-fat (HF) diet compared with animals fed a low-fat (LF) diet. The tumor-enhancing effect of HF diet was not related to body weight, since the mean body weight of the rats on the two diets was similar. In addition, no correlation was found between body weight and tumor incidence in individual rats under either dietary regimen. Since the most pronounced difference in tumor incidence between groups fed HF and LF diets was exhibited by the F344 rats, hormone analyses were performed on this group. At termination of the experiment, prolactin levels in the group fed an HF diet were significantly higher than those in the group fed an LF diet. Total estrogen levels were also significantly higher in the group fed an HF diet, compared with the group fed an LF diet, but this difference was seen only at the metestrus-diestrus stage. Regardless of diet or estrous cycle, when animals with tumors were compared with those without tumors, the former exhibited higher prolactin-estrogen (P/E) ratios. The results suggested a relationship between the ingestion of high levels of dietary fat, a high P/E ratio, and increased mammary tumor incidence.     

Inhibition of dietary fat-promoted colon carcinogenesis in rats by supplemental calcium or vitamin D3

A 2 x 2 x 2 factorial experimental design was used to investigatethe effects of supplemental calcium (Ca) (0.5% versus 1.0% ofdiet as Ca gluconate) and vitamin D₃ (D) (1000 IU/kg diet versus2000 IU/kg diet) on 1,2-dimethylhydrazine-induced colon carcinogenesisin male F344 rats promoted with a 20% corn oil diet. Animalson the high-fat (HF) diet had an increased tumor incidence comparedto the low-fat (LF) control diet (86% versus 53%, P < 0.05)and supplemental Ca or D reduced this to or below the LF incidence(HF + Ca: 53%, HF + D: 47%). However, supplemental Ca or D hadno inhibitory effect with LF diets (LF + Ca: 67%, LF + D: 60%).The results of this study indicate a possible role for supplementalCa or D in the prevention of colon cancer, effective only inHF diets.     

The effect of dietary lipid on skin tumor promotion by benzoyl peroxide: comparison of fish, coconut and corn oil

Fish or vegetable oils were fed during the promotion stage of a mouse skin carcinogenesis model in order to investigate the effects of dietary fat on tumor development. Two weeks after initiation with 10 nmol dimethylbenz[a]anthracene, SENCAR mice were divided into five groups and maintained on one of the following semipurified diets containing 10% total fat and varying the type of fat: 8.5% coconut oil (CT)/1.5% corn oil (CO); 1% menhaden oil (MO)/7.5% CT/1.5% CO; 4% MO/4.5% CT/1.5% CO; 8.5% MO/1.5% CO; or 10% CO. Promotion with twice-weekly applications of 40 mg benzoyl peroxide was begun 2 weeks later and continued for 52 weeks. No statistically significant differences in kcal food consumed or body weights were observed between diet groups. Papilloma latency, incidence and yield differed among the diet groups with the group fed the 8.5% CT/1.5% CO diet having the shortest latency and highest papilloma incidence and number. In addition, carcinoma latency and incidence was assessed and the first carcinoma appeared in the group fed 8.5% CT/1.5% CO after 20 weeks of benzoyl peroxide treatment; this group yielded the highest carcinoma incidence throughout the study. In comparison, the group fed the 10% CO diet had the longest latency period, and among the lowest papilloma and carcinoma incidence and fewest tumors. In parallel studies, ornithine decarboxylase activity, vascular permeability and hyperplasia were elevated in the epidermis of benzoyl peroxide-treated mice but the extent of the response did not correlate with the different rates of tumor formation observed among the diet groups. These data indicate that dietary fat modulates tumor promotion by benzoyl peroxide in this skin carcinogenesis model with the predominantly saturated fat diet producing the highest rates of papilloma and carcinogen formation and the polyunsaturated fat diet the lowest.     

Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding

Female 55-day-old Sprague-Dawley rats were treated with a single intravenous dose of 7,12-dimethylbenzanthracene (DMBA), 2 mg/100 g of body weight each. At 60 days of age, the rats were divided into four dietary groups (41-42 rats/group):I, 5% corn oil diet fed ad libitum; II, 20% corn oil diet fed ad libitum; III, 5% corn oil diet fed 12% less than group I; and IV, 20% corn oil diet fed 12% less than group II. The 5% and 20% corn oil diets were purified semisynthetic diets that were isonutrient on a caloric basis. All animals were housed individually in single cages; food consumption of each animal was computed daily throughout the study. Sixteen weeks after carcinogen treatment, mean numbers of mammary carcinomas per rat (+/- SE) in groups I, II, III, and IV were 4.1 +/- 0.6, 6.8 +/- 0.7, 3.0 +/- 0.3, and 4.1 +/- 0.5, respectively. Mean weight of mammary carcinomas per rat (g +/- SE) in groups I, II, III, and IV were 3.5 +/- 0.7, 8.0 +/- 1.3, 3.0 +/- 1.1, and 4.6 +/- 1.3, respectively. Mammary carcinoma number and weight were significantly (P less than .01) increased in the animals fed the 20% corn oil diet ad libitum when compared with those fed the 5% corn oil diet ad libitum; however, no significant differences in mammary tumor number or weight were observed between the animals fed a restricted, 20% corn oil diet and those fed a restricted, 5% corn oil diet. The study involving the animals fed the 12%-restricted diets was repeated (38-42 rats/group), with virtually identical results, i.e., the mean number of mammary carcinomas per rat in the groups fed the restricted 5% fat and 20% fat diets at termination of the study was 3.1 +/- 0.4 and 3.7 +/- 0.3, respectively, and the mean weight (g) of mammary carcinomas per rat was 4.3 +/- 1.2 and 4.0 +/- 1.1, respectively (no significant differences). Thus, high levels of dietary fat can significantly enhance mammary carcinogenesis in female rats, but only in animals on an ad libitum feeding protocol. A slight restriction in amount consumed (12% less than ad libitum) abolished the mammary carcinogenic differential between a high-fat and a low-fat diet.     

Effect of dietary fat on human breast cancer growth and lung metastasis in nude mice

Results from epidemiological studies have generally indicated an association of dietary saturated animal fats with human breast cancer risk. Some studies, however, have suggested a similar association for some polyunsaturated vegetable fats shown to promote both rodent mammary carcinogenesis and metastasis. This study was performed to evaluate the effects of corn oil on growth and metastasis of MDA-MB-435 human breast cancer cells, which have a propensity for metastasis. Corn oil is rich in the omega-6 fatty acid linoleic acid. Fifty-eight female athymic nude mice (NCr-nu/nu) were fed a high-fat diet (23% wt/wt corn oil; 12% linoleic acid) or a low-fat diet (5% wt/wt corn oil; 2.7% linoleic acid). Seven days after diets were started, tumor cells (1 x 10(6) were injected into a mammary fat pad. The time to appearance of solid tumors and the tumor size were recorded. After 15 weeks, the study was terminated, and autopsies were performed to determine the weight of the primary tumor and the extent of metastasis. The latent interval for tumor appearance in the animals fed the high-fat diet was shorter than that in the low-fat diet group, and the tumor growth rate in the high-fat diet group showed a small but statistically significant increase compared with the low-fat diet group. Primary tumors developed in 27 of the 29 mice on the high-fat diet and in 21 of the 29 on the low-fat diet. Of the mice with palpable primary tumors, 18 of 27 in the high-fat diet group and eight of 21 in the low-fat diet group had macroscopic lung metastases. The extent of metastasis in the high-fat diet group was independent of the primary tumor weight, but only those in the low-fat diet group with primary tumors weighing more than 2 g developed metastases. These results suggest that a high-fat diet rich in omega-6 polyunsaturated fatty acid can enhance metastasis of human breast cancer cells in this mouse model. The findings support the need for further study of the relationship between dietary polyunsaturated fats and breast cancer risk and for experiments to determine the effect on metastasis of only a 50% difference in fat intake--the dietary goal of the proposed clinical trials of low-fat dietary intervention in breast cancer patients.     

Enhancement of experimental pancreatic cancer in Syrian golden hamsters by dietary fat

The effects of dietary fat on the induction and development of pancreatic ductular adenocarcinoma were studied in randombred Syrian golden hamsters. Diets containing low-fat (LF) or high-fat (HF) levels of corn oil [4.5 or 18.0 g/385 kilocalorie (kcal)], contributing 10 or 41% of the calories, respectively, were fed either before or after a single injection of N-nitrosobis(2-oxopropyl)amine (BOP) (10 mg/kg body wt). Control hamsters were fed corn oil at a medium-fat (MD) level (9 g/385 kcal) for life. The incidence of ductular adenocarcinomas increased in both males and females (LF diet, 16%; HF diet, 34%) when the HF diet was fed after BOP treatment. The average number of carcinomas per carcinoma-bearing animal also increased (LF diet, 1.3; HF diet, 3.0), but the carcinoma incidence was not influenced by these diets being fed before carcinogen treatment. The incidence of ductular adenomas was high with all treatments and was not influenced by diet. However, the number of adenomas was increased in animals fed HF diets. In addition, the incidence of acinar cell nodules was elevated in animals fed the MF and HF diets after BOP administration. These results showed that dietary fat modified the development of experimental ductular adenocarcinoma of the pancreas.     

The combined effects of dietary fat, protein, and energy intake on azoxymethane-induced intestinal and renal carcinogenesis.

Two 3 x 3 factorial experiments were conducted to examine the effects of dietary protein (8, 16, and 32% of energy from casein) and dietary fat (12, 24, and 48% of energy from corn oil) on the initiation and promotion of azoxymethane-induced carcinogenesis in rats. For the initiation study, 33 weanling male Sprague-Dawley rats were randomized to each of nine diets fed ad libitum. Azoxymethane was administered s.c. between the fourth to sixth weeks of feeding, providing a total dose of 6 mg/100 g body weight. All rats were subsequently fed a common diet containing 16% energy from protein and 24% energy from fat for an additional 30 to 38 weeks. For the promotion study, all rats were fed a common diet containing 16% of energy from protein and 12% of energy from fat until the completion of azoxymethane administration, when 33 rats were randomized to each of nine diets varying in fat and protein content and fed these diets until sacrifice. Low-protein diets during the initiation phase were associated with increased risk of renal adenocarcinomas (P less than 0.001) and mesenchymal (P = 0.005) malignancies. No other statistically significant relationships were found between the levels of dietary fat or protein and the prevalence of malignant lesions of the small intestine, colon, or kidney in either the initiation or promotion study (although polypoid adenocarcinoma of the colon increased suggestively from 13 to 19 to 26% of rats with increasing dietary protein during initiation). Results of a multiple logistic regression analysis, combining both studies, showed that ad libitum energy intake was significantly associated with intestinal carcinogenesis. The odds of finding an intestinal adenocarcinoma increased by 6.2 +/- 2.6% (SE) for each additional kilocalorie of mean daily ad libitum intake (P = 0.014). The quintile of rats which consumed the least averaged 60 kcal/day, while the most voracious quintile averaged 74 kcal/day. This 14 kcal/day difference in mean ad libitum intake corresponded to more than a doubling (146% increase) of the odds of developing an intestinal adenocarcinoma. These studies suggest that ad libitum energy intake is a critical factor modulating experimental colon carcinogenesis.     

Comparative effects of different animal and vegetable fats fed before and during carcinogen administration on mammary tumorigenesis, sexual maturation, and endocrine function in rats

The purpose of this investigation was to determine whether diets high in animal or vegetable fat affected mammary tumorigenesis when fed to rats only prior to and during the initiation phase of carcinogenesis. Weanling 21-day-old female Sprague-Dawley rats were divided into different dietary treatment groups and were allowed to feed and libitum on one of the following diets: 5% (normal fat) corn oil; 20% (high fat) corn oil; 20% palm oil; 20% beef tallow; or 20% lard. At 52 days of age, all rats were given p.o. 7.5 mg 7,12-dimethylbenz(a)anthracene (DMBA). One week following DMBA administration, all rats were switched to the 5% corn oil control diet and were maintained on this diet for the duration of the experiment. Rats fed a 20% lard diet during the treatment period showed a significant increase in mammary tumor incidence and number 19 weeks after DMBA administration, when compared to all other dietary treatment groups. Rats fed a 20% beef tallow diet during this same time period also demonstrated enhanced mammary tumor development, during the 10- to 19-week time period after DMBA. Mammary tumor development in rats fed 20% corn oil or palm oil diets during this treatment period was similar to that of normal fat controls. Estrogens are potent stimulators of mammary tumor growth and development in rats. Because mammary tumorigenesis was enhanced in rats fed high animal, but not vegetable fat diets, it was possible that estrogens present in animal fat might be responsible for this stimulation. Further studies demonstrated however, that increased mammary tumorigenesis in rats fed diets high in animal fat could not be explained on the basis of endocrine stimulation. Average day of vaginal opening for all groups fed 20% fat diets was similar and occurred earlier than in normal fat controls. In addition, 50- to 65-day-old rats in the different dietary treatment groups showed no differences in basal or surge levels of serum prolactin, luteinizing hormone, or estradiol. Rat diestrus uterine weight also showed no significant differences among dietary treatment groups. Thus diets containing high levels of animal fat caused little if any increased estrogenic activity in rats. In conclusion, high dietary intake of lard and beef tallow, but not vegetable fat, fed from weaning until only 1 week after DMBA administration, significantly enhances mammary tumorigenesis in rats. The mechanism(s) by which animal fat induces this stimulation is not clear, but it does not appear to result from endogenous or exogenous endocrine stimulation.     

Dietary fat influences on murine melanoma growth and lymphocyte-mediated cytotoxicity

The effects of fat concentration and saturation on the growth of a B16 melanoma and lymphocyte-mediated cytotoxicity against the cells were studied with the use of inbred C57BL/6J and C3H/HeJ mice subjected to dietary manipulation before and after tumor transplantation. The tumor latency for mice initially given injections of 5 X 10(6) syngeneic B16 melanoma cells was significantly less for those mice fed at 20% fat concentration than those fed only the essential fatty acid (EFA) diet. When mice were given injections of 10(6) melanoma cells, the initiation time required for visible tumor growth in mice receiving the polyunsaturated fat (PUF) diet was significantly less than that in mice receiving the saturated fat (SF) diet. Cytolysis mediated by lymphocytes from diet-manipulated mice toward allogeneic B16 melanoma cells was greater for those mice receiving the EFA diet only and 8% SF diets than for those mice fed a diet without fat. The cytolytic response decreased immediately with the additional PUF in the diet, whereas additional SF decreased cytolytic responses only when dietary SF concentration was greater than 8%. Thus dietary fat, particularly PUF, has a significant influence on the growth and lymphocyte-mediated cytotoxicity of a murine melanoma. This effect cannot be attributed to differences in the energy content between high-fat and low-fat diets.     

Vitamin D, calcium, and mammographic breast densities.

Vitamin D and calcium are being evaluated as potential breast cancer prevention agents. This study reports on the relation of dietary vitamin D and calcium to mammographic breast densities, one of the strongest breast cancer risk factors. Participants were women ages 40 to 60 years who had had a screening mammogram in Rhode Island and eastern Massachusetts (1989-1990). Diet was assessed by semiquantitative food frequency questionnaire, and the percentage of the breast showing densities was estimated visually by a single observer without information on subjects. Multivariate logistic regression was used to compare dietary intakes of vitamin D and calcium between women classified as having few densities (< or =30% of the breast with density, n = 287) and extensive densities (> or =70% of the breast with density, n = 256). For categories of increasing vitamin D intake (<50, 50-99, 100-199, and > or =200 IU/d), adjusted odds ratios (OR) for extensive densities were 1.00 (reference), 0.51, 0.37, and 0.24, respectively (P for trend = 0.0005). For increasing calcium intake (<500, 500-749, 750-999, and > or =1,000 mg/d), adjusted ORs were 1.00 (reference), 0.63, 0.25, and 0.24, respectively (P for trend = 0.0006). Combination of higher intakes of vitamin D and calcium (> or =100 IU/d and > or =750 mg/d, respectively) were associated with a reduction of breast densities (OR, 0.28; 95% confidence interval, 0.15-0.54) compared with those consuming <100 IU/d and <750 mg/d. Increases in vitamin D and calcium intakes were associated with decreases in breast densities, suggesting that dietary vitamin D and calcium could reduce breast cancer risk possibly through influences on breast tissue morphology.     

Opposing effects of prepubertal low- and high-fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis

To determine whether dietary fat intake during childhood affects the later risk of developing breast cancer, we fed prepubertal rats between post-natal days 5 and 25 a low (16% energy) or high-fat (39% energy) diet composed mainly of n-6 or n-3 polyunsaturated fatty acids (PUFAs) originating either from corn oil or menhaden oil, respectively, in the ratios of 16-17:1 (n-6 PUFA diets) or 2-3:1 (n-3 PUFA diets). We also examined whether changes in risk are associated with perturbations in biological processes previously linked to fatty acid intake and breast cancer. Mammary tumorigenesis was induced by treating 50-day-old rats with the carcinogen 7,12-dimethylbenz[a]anthracene. When compared with the reference low-fat n-6 PUFA diet, prepubertal exposure to the low-fat n-3 PUFA diet decreased, whereas a high-fat n-3 PUFA diet increased mammary tumor incidence; the high-fat n-6 PUFA diet had no effect. Both the low and high-fat n-3 PUFA diets induced mammary epithelial differentiation by reducing the number of terminal end buds (TEBs) and increasing the presence of lobulo-alveolar structures. They also increased lipid peroxidation and reduced cyclooxygenase-2 activity. Prepubertal exposure to the low-fat n-3 PUFA diet increased apoptosis, determined using TUNEL assay, and reduced cell proliferation, determined using PCNA staining. In marked contrast, prepubertal exposure to the high-fat n-3 PUFA diet induced cell proliferation and inhibited apoptosis in the TEBs and lobular structures. The latter is consistent with the finding that pAkt, a survival factor that inhibits apoptosis, was elevated in their mammary glands. In summary, although prepubertal exposure to a low-fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast cancer risk.     

Effects of the interaction of dietary fat and protein on N-nitrosobis(2-oxopropyl)amine-induced carcinogenesis and spontaneous lesions in Syrian golden hamsters

Syrian golden hamsters were fed four diets in experiments designed to evaluate the effects of the interaction of dietary fat and protein on carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4]. The diets consisted of two levels of dietary fat [4.5 g (low fat, LF) or 18 g (high fat, HF) of corn oil/385 kilocalories (kcal)]. These levels were fed with each of two levels of dietary protein [9 g low-protein (LP) and 36 g high-protein (HP) casein/385 kcal]. The four diets were fed to two separate groups of hamsters at two different periods in their life-span. For testing of the effects of diet on tumor initiation, one group received the diets from 3 to 7 weeks of age. At 8 weeks, they were given injections sc of 10 mg BOP/kg body weight and placed on a control diet [9 g corn oil (medium fat) and 18 g casein (medium protein)/385 kcal]. The other group received control diet until 8 weeks of age, at which time they were given injections of BOP and placed on the four diets. This group was designed to test the effects of the diets on tumor development. BOP-induced lesions in the lungs, liver, common bile duct, gallbladder, and kidneys are described; results in the pancreas were reported separately. In hamsters fed the four diets after BOP treatment, the LF-LP groups had the fewest tumors, the LF-HP-fed and HF-LP-fed groups had intermediate yields of tumors, and the hamsters given HF-HP diet exhibited the largest numbers of neoplasms. Several specific tumor types showed a similar pattern. For example, the pulmonary adenoma incidence, which was low in the non-BOP-treated hamsters, was higher in the HF-HP group than in those fed LF-HP diet after BOP, but it was not influenced by fat at the LP level. In addition, renal adenomas were observed at a low incidence in non-BOP-treated hamsters and in hamsters fed LF-LP levels before or after BOP treatment (0.5% incidence) but were present at an 8% incidence in all other BOP-treated groups. The incidence of biliary cystic adenomas was highest in male hamsters that received HF diets, irrespective of BOP treatment, and BOP treatment resulted in increased yields of this lesion in females only in groups given HF-LP diet.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of Esculetin on Incidence, Proliferation, and Cell Kinetics of Mammary Carcinomas Induced by 7,12-Dimethylbenz[α]anthracene in Rats on High- and Low-fat Diets

The effects of a high-fat diet and esculetin were investigated on 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Rats were given a 5-mg dose of DMBA. Seven days later, they were fed either a high-fat (20% soybean oil) or low-fat (0.5% soybean oil) diet. A half of the rats received diets containing 0.03% esculetin. Esculetin significantly inhibited tumor incidence, growth and cell kinetics of the tumor in the rats fed the high-fat and the low-fat diets. Our findings indicate that DMBA-induced mammary tumorigenesis is affected by lipoxygenase products.     

Differential effects of tranylcypromine and imidazole on mammary carcinogenesis in rats fed low and high fat diets

Neoplastic development in the rat mammary gland can be suppressed by inhibition of the activity of several enzymes involved in eicosanoid biosynthesis. In order to investigate the potential utility of prostacyclin and thromboxane synthetases as targets for mammary cancer chemoprevention, experiments were conducted to determine the influence of tranylcypromine (TCP), an inhibitor of prostacyclin synthetase, and imidazole (IMI), an inhibitor of thromboxane synthetase, on mammary carcinogenesis induced in rats by N-methyl-N-nitrosourea. Fifty-day-old female Sprague-Dawley [Hsd:SD(BR)] rats received a single s.c. dose of 0 or 40 mg of N-methyl-N-nitrosourea per kg of body weight. Beginning 7 days after carcinogen administration, groups of rats were fed isoenergetic, casein-based diets containing 3 or 20% corn oil (w/w), supplemented with (per kg of diet) 10 mg of TCP, 1000 mg of IMI, or sucrose carrier only. TCP reduced mammary carcinoma multiplicity in rats fed the 20% corn oil diet, but had no effect in rats fed the diet containing 3% fat. By contrast, supplementation with IMI increased mammary cancer incidence in the group fed the 20% fat diet and increased carcinoma multiplicity in the 3% fat group to the levels seen in rats fed the 20% fat diet. These data suggest that inhibition of prostacyclin synthetase, but not thromboxane synthetase, may present a useful mechanism for mammary cancer chemoprevention in animals consuming a diet high in fat. Furthermore, the differential effects of TCP and IMI in rats fed low and high fat diets suggest that the action of dietary fat in mammary cancer induction may involve influences on the arachidonic acid cascade.     

Effects of high fat diet and cholecystokinin receptor blockade on pancreatic growth and tumor initiation in the hamster

The mechanism by which high-fat diet potentiates pancreaticcancer is not known, but trophic hormones may be involved. Inpreliminary growth studies, hamsters fed a high fat diet (17.5%lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P< 0.01) in pancreatic weight compared to controls on lowfat diet (2.5% lard, 2.5% corn oil). A significant increasewas also seen at 28 days. Similar increases were seen in pancreaticDNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05)at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were2.5 fold higher in the animals fed high fat (P < 0.01). Infusionof the CCK antagonist MK329 (25 nmol/kg/h) completely abolishedthe increase in pancreatic weight, pancreatic DNA and pancreaticRNA. The effect of CCK receptor blockade during the initiationperiod of carcinogenesis was investigated in hamsters fed thesame diets used in the growth studies. One hundred animals receiveda single injection of N-nitrosobis(2-oxopropyl)amine, (BOP,20 mg/kg). Half of the hamsters in each diet group receiveda 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 daysbefore carcinogen administration. At the time of death, 55 weeksafter carcinogen administration, non-fasting plasma CCK levelswere 31% higher in the high fat fed hamsters than in the lowfat fed animals (P < 0.01). The high-fat diet group had a3-fold increase in total cancer incidence and a 5-fold increasein advanced lesions (adenocarcinomas). Tumor incidence and yieldwere not changed in either diet group by CCK-receptor blockadeduring the initiation period. Cholecystokinin appears to mediatethe short-term trophic effect that high-fat feeding has on thepancreas. However, potentiation of pancreatic cancer by high-fatdiet in the hamster cancer model does not appear to be influencedby endogenous cholecystokinin at the time of tumor induction.     

Both dietary calorie and fat affect the growth of transplanted mammary-tumors in riii/sa mice - the effect of calorie is more profound than the effect of fat

The effects of dietary calories and/or fat on the growth of mammary tumor transplants, their expression of mouse mammary tumor virus (MMTV) and the incidence of lung metastasis were examined in RIII/Sa mice. Starting at 3-4 weeks of age, groups of female mice were fed either high isocaloric diets (16 kcal/day/mouse) containing 25% or 5% corn or fish oil or low isocaloric (10 kcal/day/mouse) diets containing 25% or 5% fish or corn oil. After one week, small pieces (2x2x2 mm) of tumor tissue, prepared from a transplantable mammary tumor, were inserted into the fourth pair of mammary glands of mice, and the mice maintained on their respective diets until sacrifice. All mice developed palpable tumors during a period of 3-4 weeks. After 12 weeks, all those mice that were assessed for tumor burden were sacrificed, tumor weight in each mouse determined, and the level of the expression of MMTV in the tumors evaluated by dot blot hybridization. Our results show that low isocalorie diets, regardless of the type or amount of fat, inhibited tumor growth by at least 60% in comparison to high isocalorie diets. However, mice fed low isocaloric diets containing fish oil were also found to produce smaller tumors (20-40%) as opposed to those mice fed similar, but corn oil containing diets. Fatty acid analyses of mammary tumors and liver tissue of mice fed corn oil and fish oil containing diets revealed that while normal and tumor tissues from both groups contained high levels of polyunsaturated fatty acids, the tissues of mice fed corn oil had the n-6, whereas the mice fed fish oil had the n-3 family of fatty acids. The levels of MMTV expression were found to be unaffected by either caloric or fat content in the diet. In a separate set of experiments, the effect of a low calorie diet on lung metastasis was determined, It was found that mice fed a low calorie diet produced significantly less metastatic lung nodules than those mice fed a high calorie diet: the mean survival time for the former group of mice was 106 days, as compared to only 71 days for the latter group of mice. In conclusion, we suggest that the amount of calories in a diet is more important than the amount or the type of fat in suppressing the growth of transplanted tumors and that a low calorie diet may also lower the incidence of lung metastasis.