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 restricted caloric intake on azoxymethane-induced colon tumor incidence in male F344 rats

The effect of 30% caloric restriction on azoxymethane (AOM)-induced colon carcinogenesis was investigated in male F344 rats. Starting at 5 weeks of age, groups of animals were fed ad libitum a high-fat (23.5%) semipurified diet. At 7 weeks of age, all animals except the vehicle-treated groups were s.c. injected with AOM (15 mg/kg body wt, once weekly for 2 weeks). Four days after the second AOM injection, groups of animals were continued on high-fat diet and fed ad libitum (ad libitum group) whereas other groups were restricted to 70% of total calories (calorie-restricted group) consumed by the ad libitum group, but received same amounts of fiber, vitamins, and minerals. Thirty-two weeks after AOM injections, all animals were necropsied. The animals in the calorie-restricted group developed significantly fewer colon tumors and had a lower colon tumor incidence than did the rats in the ad libitum group. The size of colon tumors was also reduced in the calorie-restricted group.     

Influence of dietary fat, caloric restriction, and voluntary exercise on N-nitrosomethylurea-induced mammary tumorigenesis in rats

The effect of dietary fat, energy restriction, and exercise on N-nitrosomethylurea (NMU:CAS:684-93-5)-induced mammary tumorigenesis in female F344 rats was investigated. Rats were fed the NIH-07 diet until N-nitrosomethylurea administration on Day 50 of age, when they were transferred to six treatment groups. Three sedentary groups were fed either high-fat (20%, w/w), medium-fat (10%), or low-fat (5%) diets ad libitum (HFAL, MFAL, LFAL, respectively); two sedentary groups were fed high fat and medium fat diets restricted to 75% of the food consumed by their ad libitum counterparts (HFR, MFR), and one group was fed a HFAL diet but allowed free access to an activity wheel (HFEX). Tumor yields among the three ad libitum sedentary groups were significantly greater in the HFAL and MFAL groups when compared to the LFAL group. Dietary restriction reduced tumor yields by more than 90% of ad libitum controls regardless of fat intake. Voluntary exercise reduced tumor yields and delayed time of tumor appearance in HFEX animals to levels similar to those found in LFAL animals. Animals with voluntary access to exercise wheels averaged between 1.03 and 2.85 miles/day, consumed more food (+18%), and exhibited greater weight gain (+13%) than their sedentary counterparts. Restricted animals exhibited significantly decreased body weight gains (-15%) compared to their ad libitum counterparts, but no differences in weight gains were detected among the HFAL, MFAL, and LFAL groups, despite widely varying amounts of fat intake. Body composition studies indicated that body fat content was not influenced by the quantity of fat consumed in the diet, but was significantly reduced by caloric restriction (-20 to 26%) and exercise (-20%). While the precise mechanisms underlying the tumor-promoting effects of HFAL diets and the antipromoting effects of energy restriction and exercise remain to be elucidated, available evidence suggests that these effects are not due to alterations in energy homeostasis per se, but may instead be exerted indirectly, and perhaps independently via endocrine, paracrine, or neurohormonal mechanisms.     

Combined effect of intravenous hyperalimentation and chemotherapy on experimental meningioma

Combination effects of intravenous hyperalimentation (IVH) and chemotherapy were studied in rats with meningeal carcinomatosis. Sprague-Dawley rats were inoculated intracisternally with 1 X 10(4) Walker 256 carcinosarcoma cells. Animals were divided into five groups of 10 to 12 animals per group: 1) no treatment; 2) cyclophosphamide 30 mg/kg i.v. at 5 days after tumor inoculation (Day 5); 3) IVH (Day 5 to Day 10); 4) cyclophosphamide (Day 5) and IVH (Day 5 to Day 10); and 5) cyclophosphamide (Day 5) and IVH (Day 10 to Day 15). The group of IVH alone reduced survival time significantly (p less than 0.001) compared with no treatment group. Cyclophosphamide alone increased survival time significantly (p less than 0.001) in comparison with no treatment group. Combination of cyclophosphamide (Day 5) and IVH (Day 5 to Day 10) did not prolong survival time compared with cyclophosphamide alone. However, IVH (Day 10 to 15) in combination with cyclophosphamide (Day 5) prolonged survival time significantly (p less than 0.001) in comparison with cyclophosphamide alone. Mean body weight was reduced maximally at 5 to 10 days after cyclophosphamide injection. However, no reduction of body weight was noted while animals were on IVH. The present data appears to indicate that IVH may reduce the side effects of cyclophosphamide and may prolong the survival time.     

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.     

Total parenteral nutrition and inhibition of gluconeogenesis on tumor-host responses.

Rats bearing the Morris hepatoma No. 7777 were randomized into three treatment groups. Two of the groups received a nutritionally complete liquid formula diet per os ad libitum. One of these two groups received hydrazine sulfate (HS; an inhibitor of gluconeogenesis) twice daily (15 mg/kg) for 5 days. A third group of tumorous rats received the HS therapy and was given the liquid diet parenterally for 5 days. Tumorous rats fed per os, especially with HS therapy demonstrated inhibition of tumor growth, reduction of body and carcass weight, anorexia and decreased nitrogen retention. The combination of parenteral feeding and HS therapy sustained body and carcass weight with high nitrogen retention but stimulated tumor growth and was associated with liver toxicity. These results support the concept that cancer cachexia involves 'a systemic energy-losing cycle dependent on an interplay of tumor glycolysis and gluconeogenesis'.     

Continuous intravenous fucose therapy in rat mammary cancer. II

Twenty-five Lewis-Wistar rats, weighing 500 to 525 gm each, received a transplantable mammary tumor which spontaneously arose in this strain; two days later, they were equipped with a silastic catheter inserted into the superior vena cava, the catheter protected by a specially designed harness allowing unrestricted movement of the animals. On the fifth day after tumor implantation, continuous intravenous infusions were begun, five rats serving as control and receiving only saline, twelve rats receiving glucose and eight rats receiving fucose. All 25 animals tolerated the procedure with no toxicity in any group as determined by animal inspection, measurement of blood urea nitrogen and of serum glutamic pyruvate transaminase. There was no significant weight change during the course of the experiment. On completion of infusion, tumors in rats receiving 20% fucose showed a statistically significant smaller mean diameter as compared to both controls and rats receiving intravenous glucose. After cessation of the ten-day infusion the tumors in the fucose-treated rats remained significantly smaller than those in their glucose counterparts or controls. Attendant on intravenous fucose therapy was a definite increase in total oral intake and urinary output. Twenty-one days after conclusion of intravenous therapy all animals were sacrificed, and the tissues of those who received fucose were found to have a statistically significantly increased level of serum protein-bound fucose.     

Dietary protein intervention during the postdosing phase of aflatoxin B1-induced hepatic preneoplastic lesion development

The effects of high and low dietary protein intervention on the growth and development of hepatic preneoplastic lesions were examined. Inbred male F344 rats fed a semipurified (AIN-76) 20% casein diet were given doses orally of aflatoxin B1 (10 doses, each 250 micrograms/kg). One week after the last dose, animals were fed diets containing either 5 or 20% casein. Animals fed a 5% casein diet throughout the 12-week postdosing period had a marked reduction in development of gamma-glutamyltransferase-positive foci. Animals fed a 20% casein diet throughout the same period had the highest response. Groups fed the 5% casein diet for half of the postdosing period and 20% for the other half had intermediate responses. The data show that the high response observed in animals fed a high-protein diet can be inhibited by the postinitiation intervention of a low-protein diet. Likewise, the low response observed in the animals fed a low-protein diet was increased by the introduction of a high-protein diet late in the experiment.     

Effects of nutritional depletion and repletion on plasma methotrexate pharmacokinetics

Clinically, a relationship exists among nutritional status, drug responsiveness, and host toxicity, but the effects of nutrition on chemotherapy drug metabolism are relatively unknown. This article evaluates the effect of malnutrition and nutritional repletion on plasma methotrexate (MTX) pharmacokinetics. In Study I, 55 non-tumor-bearing rats were fed regular diet (RD) (N = 27) or protein-free diet (PFD) (N = 28) for 10 days. On day 10, MTX 20 mg/kg was injected intraperitoneally and four to six animals in each group were killed at 30 minutes, 1, 2, 6, 24, and 48 hours following MTX administration. Plasma MTX was measured by dihydrofolate reductase enzyme inhibition assay and was found to be significantly elevated (P less than 0.01) in PFD animals as compared with RD animals at 1 and 2 hours following MTX injection. In Study II, 87 tumor-bearing rats were fed RD (N = 29) or PFD (N = 58) for 10 days. At this time, 27 PFD rats were switched to RD (PFD----RD), while 31 rats remained on PFD. MTX 20 mg/kg was injected intraperitoneally and six to eight rats in each group were killed at 1, 2, 6, and 24 hours post-MTX injection. Mean levels were found to be significantly elevated at 2, 6, and 24 hours in PFD (P less than 0.01) and PFD----RD (P less than 0.05) compared with RD rats. Several investigators have shown that increased plasma MTX levels at 24 and 48 hours after drug administration correlates with host toxicity in patients receiving chemotherapy. In this experimental study, malnutrition delayed plasma MTX clearance, and nutritional repletion for 2 days was insufficient to return MTX pharmacokinetics to normal. These results in experimental animals suggest an explanation for increased MTX toxicity in malnourished individuals.     

Comparison between continuous intravenous and oral administration of 5-FU with LV

In case of 5-fluorouracil (5-FU)/leucovorin (LV) treatment, which is one of the most effective forms of chemotherapy for colorectal carcinoma, 5-FU is usually continuously infused from the venous route. However, since this continuous infusion limits the patients' active daily life, oral administration is preferable. In the present study, we evaluated the efficacy and side effects of orally administered 5-FU/LV. MATERIAL AND METHODS: In the continuous intravenous infusion group (civ group), colon 26 bearing mice were cannulated into central vein from external jugular vein. From this route, either 5, 10, or 20 mg/kg of 5-FU was continuously infused for 7 days (n = 6). In another group, either 10, 20, 40 mg/kg of 5-FU was infused orally (po group, n = 6). The other 6 animals were used for the non-treatment group. In the next series, 100 mg/kg of LV was added for each group above. Tumor volume, thymidylate synthase inhibition rate (TSIR) and body weight were measured at the end of infusion. During the experimental period, mice had free access to chow and water. RESULTS: The tumor/control (T/C) volumes ratio showed that approximately twice the orally administered 5-FU dose had an anti-tumor effect equal to that of 5-FU administered intravenously. Synergic antitumor effects by LV were only revealed in the civ group. Significant body weight loss was recognized only in the po group at a 5-FU dose of more than 20 mg/kg. In summary, since the modulation effect of LV was recognized only with continuously intravenous infusion of 5-FU, further improvement of oral administration is required in the LV/5-FU combination therapy.     

Effect of dietary sodium ascorbate on 1,2-dimethylhydrazine- or methylnitrosourea-induced colon carcinogenesis in rats

The effect of dietary sodium ascorbate (SA) on colon carcinogenesisevoked by 1,2-dimethylhydrazine (DMH) or N-methyl-N-nitrosourea(MNU) was studied in female F344 rats. Animals were fed dietscontaining 0, 0.25 and 1% of SA and given s.c. a single doseof 150 mg DMH/kg body wt., 10 weekly s.c. injections of 20 mgDMH/kg body wt. or intrarectal administration of 2 mg MNU, twicea week for 2 weeks. The incidence of colon and kidney tumorswas lower in rats fed the 0.25 or 1% SA and treated with a singledose of DMH than in the animals fed the diet without SA; however,the tumor incidences did not differ between the SA- and controldiet-fed animals and treated with multiple doses of DMH or MNU.     

Effect of dietary fiber on azoxymethane-induced intestinal carcinogenesis in rats.

The effect of alfalfa, bran, and cellulose on intestinal tumor formation and fecal billary steroid levels was studied in male Sprague-Dawley rats given injections of azoxymethane (AOM). Animals received weekly injections of 8 mg AOM/kg and were fed diets containing 10% fiber (wt/wt) and 35% beef fat or 20 or 30% fiber and about 6% beef fat. Control animals in each instance were fed fiber-free diets. The addition of 10% fiber to the high-fat diet did not significantly reduce the intestinal tumor frequency (average No. of tumors/rat). However, addition of 20 or 30% fiber to the 6% fat diet significantly reduced the intestinal tumor frequency. The concentration of fecal biliary steroids (mg/g dry feces) was significantly lowered in the groups with reduced tumor frequencies, whereas the total excretion of fecal biliary steroids (mg/day) did not show a similar correlation. These observations suggest that intestinal tumor frequency can be reduced by increased dietary fiber only when fat intake is not at a high level. The effect of fiber may be due to dilution of promoters and/or carcinogens in the intestinal tract.     

Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin

The effects of dietary supplementation of flavonol quercetin on both 7,12-dimethylbenz(a)anthracene (DMBA)- and N-nitrosomethylurea-induced mammary cancer in female Sprague-Dawley rats were determined. Quercetin diet was started 1 wk before intragastric instillation of DMBA (65 mg/kg of body weight) or i.v. injection of N-nitrosomethylurea (50 mg/kg of body weight) and was continued during the entire period (20 wk) of the experiment. Dietary quercetin inhibited both the incidence and the number of palpable rat mammary tumors; rats fed on 2% quercetin had 25% less incidence of mammary cancer, while the average number of mammary tumors per rat was reduced by 39% at 20 wk post-DMBA administration compared to animals on a control diet. In a separate experiment, a 5% quercetin diet elicited a greater inhibitory effect on the induction of rat mammary tumors by DMBA than was observed with a 2% quercetin diet. The inhibitory effect of quercetin on mammary tumor incidence in rats on 2% and 5% diets and on tumor multiplicity in animals on a 5% diet was statistically significant (P less than 0.05). In addition, the risk of the development of a palpable tumor (as determined by the nonparametric estimate of the hazard function) in the quercetin-fed group was lower than the group on control diet throughout the course of the experiment. Furthermore, 5% dietary quercetin significantly inhibited (P less than 0.05), although to a lesser extent than observed in DMBA-induced tumor formation, both the incidence and the number of palpable mammary tumors per rat induced by N-nitrosomethylurea. Dietary quercetin did not elicit any detectable sign of toxicity. The gain in body weight in rats on the quercetin diet and the quantity of diet consumed per rat per week were similar to those for rats on the control diet.     

Effect of dietary corn bran and autohydrolyzed lignin on 3,2'-dimethyl-4-aminobiphenyl-induced intestinal carcinogenesis in male F344 rats

The effect of dietary corn bran and autohydrolyzed lignin on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced intestinal carcinogenesis was studied in male inbred F344 rats. Groups of weanling rats were fed semipurified diets containing 15% corn bran or 7.5% lignin or a semipurified diet without these fibers (control diet). At 7 weeks of age, all animals, except vehicle-treated controls, were given sc injections of 50 mg DMAB/kg body weight/week for 20 weeks. All animals were autopsied 20 weeks after the last injection of DMAB. The incidence of colon tumors (percentage of animals with tumors) and colon tumor multiplicity (tumors/animal) were increased in rats fed the corn bran diet as compared to the tumor incidence and multiplicity in rats fed the control diet. The incidence of small intestinal tumors was slightly lower in rats fed the corn bran diet as compared to the incidence in rats fed the control diet. The concentrations (mg/g dry feces) of fecal deoxycholic acid and total bile acids and the daily output of fecal deoxycholic acid, lithocholic acid, hyodeoxycholic acid, and total bile acids were increased in rats fed the corn bran diet as compared to the concentrations and daily output in rats fed the control diet. The incidence and multiplicity of small intestinal tumors as well as the number of colon adenocarcinomas per tumor-bearing animal were lower in animals fed the lignin diet than in those fed the control diet. Lignin had no effect on the concentrations of fecal bile acids, but the daily output of total bile acids was increased in animals fed the lignin diet as compared to the daily output in rats fed the control diet. This study thus indicates that the protection against colon cancer depends on the type of fiber.     

Effect of different levels of calorie restriction on azoxymethane-induced colon carcinogenesis in male F344 rats

Epidemiological and animal model studies indicate that increased calorie intake increases the risk for colon cancer development. Previous studies in animal models restricted the calorie intake severely, and none of these studies have investigated a dose-response effect of different levels of calorie restriction on colon carcinogenesis. The present study was designed to investigate the effect of various levels of calorie restriction on colon carcinogenesis in male F344 rats fed the low and high fat diets and the effect of these diets on the activities of colonic mucosal and tumor ornithine decarboxylase (ODC) and protein tyrosine kinase. Starting at 5 weeks of age, groups of male F344 rats were fed the low fat or high fat diets ad libitum. At 7 weeks of age, all animals except the vehicle-treated groups were given s.c. injections of azoxymethane (AOM) (15 mg/kg body weight, once weekly for 2 weeks). Four days after the second injection, groups of animals were restricted to 90, 80, or 70% of total calories consumed by the high fat ad libitum group (i.e., 10, 20, and 30% calorie restriction, respectively). In the low fat groups, animals were restricted to 80% of total calories consumed by the low fat ad libitum group (i.e., 20% restriction). Thirty-six weeks after AOM injections, all animals were necropsied and colon tumors were used for histopathology and ODC and protein tyrosine kinase analysis. In the second experiment, the protocol was the same as above except that the animals were sacrificed 5 days after the second AOM injection and colonic mucosal ODC and protein tyrosine kinase activities were assayed. The incidence and multiplicity of colon tumors were significantly inhibited in animals fed the high fat 20% calorie-restricted and high fat 30% calorie-restricted diets, as compared to those fed the high fat ad libitum diet. The regression coefficient representing the dose-response effect of different levels of calorie restriction in both high fat groups is significant. Results also indicate that AOM treatment significantly increased the colonic mucosal ODC and protein tyrosine kinase activities. This stimulation was inhibited by feeding the calorie-restricted diets. ODC and protein tyrosine kinase activities were lower in the colon tumors of animals fed the calorie-restricted diets.     

Procarbazine carcinogenicity in methotrexate-treated or lipotrope-deficient male rats

Procarbazine hydrochloride (PCZ), a chemotherapeutic agent used extensively to treat Hodgkins disease and other tumors, induces leukemia, lymphoma, mammary gland and other solid tumors in rodents and non-human primates and is strongly implicated as a leukemogen in humans. Lipotrope (choline and methionine) deficiency is a powerful potentiator of chemical carcinogenesis in liver and, under some conditions, in other tissues in rodents. Methotrexate (MTX), another commonly used chemotherapeutic agent, interferes with one-carbon metabolism and limits availability of lipotropes. Studies of PCZ carcinogenesis in lipotrope-deficient or MTX-treated male rats are reported, showing that both deficiency and MTX increased PCZ carcinogenicity in the mammary gland. In addition, PCZ was found to induce abnormalities of hepatic choline metabolism. Weanling male Sprague-Dawley rats were fed control (C) or lipotrope-deficient (D) diet. After 3 weeks, C and D rats were given PCZ, MTX, the two drugs together or 0.9% saline by i.p. injection. Doses were 0.2 or 0.5 mg MTX/kg or 25 mg PCZ/kg, given 2 or 3 days per week for 5 or 14 weeks. After 5 weeks of drug treatment livers were assayed for choline, phosphatidylcholine, phosphocholine (PCho), glycerophosphocholine and betaine. PCZ perturbed choline metabolism, increasing hepatic choline and PCho in deficient or MTX-treated rats and, to a smaller extent, in rats fed control diet. MTX markedly enhanced the effect of PCZ on choline metabolism. PCZ-induced mammary tumor incidence was increased 50-70% by lipotrope deficiency or by MTX. In PCZ-treated rats, cumulative probability of bearing a mammary tumor was significantly increased by lipotrope deficiency (P = 0.05), and was increased similarly but not significantly by MTX (P = 0.1). Cumulative tumor numbers per group in PCZ-treated rats were significantly greater in both deficient and MTX-treated rats compared to rats fed control diet (P less than 0.005). Incidences of leukemia, lymphoma and Zymbal's gland tumors induced by PCZ were not significantly altered by diet or MTX.     

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.     

Selenium and difluoromethylornithine additively inhibit DMH-induced distal colon tumor formation in rats fed a fiber-free diet

We investigated the effects of difluoromethylornithine, an inhibitorof ornithine decarboxylase (ODC) and selenium supplementationon tumor formation induced by the carcinogen 1, 2-dimethylhydrazine(DMH) in Sprague-Dawley rats. A biochemical link between polyaminebiosynthesis and selenium metabolism to its cancer preventativeform has been suggested by the common requirement of S-adenosylmethio-nine.One-hundred and twenty male Sprague-Dawley rats were dividedinto experimental (n = 80) and control (n = 40) groups. Experimentalanimals received DMH 20 mg/kg s.c. for 20 weeks. Animals werefed either a regular diet (selenium content 0.2 p.p.m.) or ahigh selenium diet (5 p.p.m.) with or without 0.2% DFMO in thedrinking water. At death, week 30, animal weights within experimentalor control groups were not different between the four diet treatmentgroups. Tumor number and incidence in the proximal colon wasnot affected by DFMO treatment, selenium supplementation orthe combined treatment. In contrast, in the distal colon, 19tumors developed in the DFMO treated group, 22 tumors in thehigh selenium group and only 12 tumors in the combined highselenium/DFMO treatment group compared to 32 tumors in the regulardiet group. Similarly, tumor incidence was decreased by DFMOand selenium supplementation and their effects were additive.In control animals, ODC activity was decreased by DFMO treatmentand selenium supplementation in the distal colon and liver,but not the proximal colon. ODC activity of tumor tissue wasgreater than normal colon tissue from diet paired animals forproximal and distal colon, except for distal colonic tumorsin the high selenium/DFMO treatment group. Polyamine content,however, did not correlate with ODC activity in normal or neoplastictissue. In general, S-adenosylmethionine levels from normalcolon and liver tissue were unaffected by diet treatment. Seleniumsupplementation in combination with DFMO treatment selectivelyinhibited distal colon tumor formation in rats fed a fiber-freediet.     

Growth hormone inhibits tumor metastasis

The effect of growth hormone on tumor growth and metabolism in the tumor-bearing host is unknown. This study was done to determine the effect of recombinant growth hormone on primary tumor growth, tumor metastasis, and carcass weight in tumor-bearing animals. Twenty-seven female Lobund/Wistar rats with subcutaneous prostate tumor implants (PA-III) were randomized to receive a standard protein diet (22.0% protein; 4.27 kcal/g) or an isocaloric, protein-depleted diet (0.03% protein; 4.27 kcal/g) ad libitum orally. One half of the animals in each group were randomized to receive daily injections of either recombinant growth hormone (1000 mU/kg/day intramuscularly) or placebo (saline) for 14 days. A significant increase in body weight was observed in growth hormone-treated animals without acceleration of primary tumor growth. Spontaneous pulmonary metastasis was inhibited significantly in animals in both dietary groups treated with growth hormone. Thus, growth hormone selectively supports host growth and inhibits pulmonary metastasis in this tumor-bearing animal model. The potential metabolic effects and clinical consequences of treating cancer patients with growth hormone is discussed.     

Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.