Enhancement of pancreatic carcinogenesis by a dietary unsaturated fat in rats treated with saline or N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine

The effect of diets high in an unsaturated fat on the enhancement of pancreatic carcinogenesis in saline-treated rats and in rats treated with N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) was examined. Young male LEW rats were treated with a single dose of HPOP (160 mg/kg body wt) or saline, fed diets containing 5 or 20% corn oil, and then autopsied 12 months later. The pancreata of HPOP-treated rats fed the diet with 5% fat contained multiple foci and nodules of atypical acinar cells (AACN), acinar cell adenomas, and localized carcinomas. Rats fed the diet with 20% fat developed a similar spectrum of pancreatic lesions and also developed carcinomas that showed local invasion or metastasis to regional lymph nodes. The incidence and multiplicity of localized carcinomas was significantly higher in the group that was fed the high-fat diet. HPOP also induced neoplasms in the liver, lungs, and kidneys, but none of these had a higher incidence in the group fed the high-fat diet. Among rats that received no carcinogen, the incidence of AACN was high, but the multiplicity of these lesions was low, an average of three per pancreas in groups fed both levels of fat; however, the average area of AACN transections was larger in the high-fat diet group. One acinar cell adenoma and 1 carcinoma developed in the group of 11 rats fed the 20% corn oil diet, whereas no neoplasms developed in the group of 12 rats fed the 5% corn oil diet. Although the incidence of pancreatic neoplasms is not significantly different in these 2 groups, the data are consistent with the hypothesis that initiated foci are promoted to grow and become neoplasms in the pancreas of rats that are fed diets with a high content of unsaturated fat--as was demonstrated in the HPOP-treated rats.     

Effect of different levels of dietary corn oil and lard during the initiation phase of colon carcinogenesis in F344 rats

The effect of various levels of polyunsaturated fat (corn oil) and saturated fat (lard) fed during the initiation stage of colon carcinogenesis was studied in male F344 rats. The animals were fed the diets containing 5, 13.6, and 23.5% corn oil or lard 2 weeks before, during, and until 1 week after sc injection of 15 mg azoxymethane [(AOM) CAS: 25843-45-2]/kg body weight, once weekly for 2 weeks (designated as initiation). One week after AOM treatment, groups of animals were transferred to their respective 5% corn oil or lard diets. Additional groups consuming 5% corn oil or lard were transferred to 23.5% corn oil or lard, respectively (post-initiation stage). All animals were fed these diets until the termination of the experiment. Fecal bile acids and colonic mucosal ornithine decarboxylase activity were measured in vehicle-treated animals fed the experimental diets for 14 weeks. Body weights and intakes of total calories, protein, nonnutritive fiber, and micronutrients were comparable among the various dietary groups. The animals fed the 23.5% corn oil diet during the postinitiation stage had a higher incidence of colon tumors than did those fed the 5% corn oil diet, whereas feeding of 23.5 and 13.6% corn oil diets during the initiation stage had no effect. In contrast, animals fed the 23.5 and 13.6% lard diet during the initiation stage and 23.5% lard diet during the postinitiation stage developed more colon adenocarcinomas than did those fed the 5% lard diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid and the activity of colonic mucosal ornithine decarboxylase activity were higher in animals fed the 23.5% corn oil or lard diet during the postinitiation compared to the levels in animals fed the 5% corn oil or lard diet.     

Effect of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis.

The effect of dietary menhaden oil containing omega-3 fatty acids and corn oil rich in omega-6 fatty acids fed during the initiation and/or postinitiation stages of colon carcinogenesis was investigated in male F344 rats. At 5 weeks of age, all animals were divided into seven groups (39 rats/group) and fed the semipurified diets containing 5% corn oil (LCO), 23.5% corn oil (HCO), or 18.5% menhaden oil plus 5% corn oil (HFO). At 7 weeks of age, all animals except the vehicle (normal saline)-treated groups were given two weekly s.c. injection of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight, once weekly. Three days after the second injection of AOM, groups of animals fed LCO, LCO, HCO, HCO, HCO, HFO, or HFO diets were transferred, respectively, to LCO, HCO, LCO, HCO, HFO, HCO, or HFO and continued on these diets until termination of the experiment. All animals were necropsied 42 weeks after carcinogen treatment. Body weights of animals fed various experimental diets during the initiation and postinitiation periods were comparable. As expected, the HCO diet fed during the postinitiation period significantly increased the AOM-induced incidence and multiplicity of colon adenocarcinomas, whereas the HCO diet fed during the initiation phase of carcinogenesis had no effect. Colon tumor incidence and multiplicity were significantly reduced in groups fed the HFO diet at either initiation and/or postinitiation phases of carcinogenesis as compared with those fed the HCO diet. Whereas the precise mechanisms producing the difference between the high menhaden oil (HFO) diet as compared with high corn oil (HCO) diet 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, respectively.     

Modulation of dietary fat-promoted pancreatic carcinogenesis in rats and hamsters by chronic coffee ingestion

The effect of chronic coffee ingestion on dietary fat-promoted pancreatic carcinogenesis was investigated in rats and hamsters. Rats were given a single i.p. injection of 30 mg azaserine per kg body weight at 19 days of age. Hamsters were injected s.c. with 20 mg N-nitrosobis(2-oxopropyl)amine (BOP) per kg body weight at 6 and 7 weeks of age. The animals were fed a semi-purified diet high in unsaturated fat (25% corn oil) either in combination with coffee or not. Coffee was provided instead of drinking water. A separate group maintained on a diet low in unsaturated fat (5% corn oil) was included as extra controls. The rats and hamsters were given their diets and coffee after treatment with carcinogen. Terminal autopsy of rats was 15 months after azaserine treatment and of hamsters 12 months after the last injection with BOP. In rat pancreas, the numbers of adenomas and carcinomas were significantly lower in the group maintained on the combination of a high-fat diet and coffee than in the high-fat group without coffee, while in the latter group the number of adenomas and carcinomas had significantly increased as compared to the low-fat controls. In hamsters, the number of ductal/ductular adenocarcinomas had significantly increased in the high-fat group as compared to the low-fat controls. The inhibitory effect of coffee on dietary fat-promoted pancreatic carcinogenesis was also noticed in this species but was less pronounced than in rats. It was concluded that chronic coffee consumption has an inhibitory effect on dietary fat-promoted pancreatic carcinogenesis in rats and hamsters. More research is needed to elucidate the mechanism by which coffee (constituents) modulates carcinogenesis.     

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.     

Comparison of the effects of dietary beef tallow and corn oil on pancreatic carcinogenesis in the hamster model

We previously reported an enhancement of pancreatic carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters fed diets containing high levels of corn oil. The research presented here compared diets high in corn oil with those high in beef tallow in the enhancement of pancreatic carcinogenesis. Pancreatic cancer was induced with 20 mg BOP/kg body wt, s.c. administered at 8 weeks of age. One week later, hamsters were assigned to one of five diet treatments: (i) 4.3% corn oil (control); (ii) 20.5% corn oil (high corn oil); (iii) 0.5% corn oil + 3.8% beef tallow (low beef tallow); (iv) 0.6% corn oil + 19.9% beef tallow (high beef tallow); and (v) 5.1% corn oil + 15.4% beef tallow (high fat mixture). These diets were fed until the study ended 84 weeks after BOP treatment. Hamsters were trained through pair feeding to consume the same calorie allotment as the control corn oil group. By the end of the experiment, BOP-treated hamsters that were fed diets containing beef tallow were consistently heavier than those fed corn oil. Survival was longer in hamsters fed the high-beef tallow and high-fat mixture compared with the other diet groups. Tumor data were age adjusted to correct for survival differences. Pancreatic adenoma incidence and multiplicity (no./effective animal) were higher in hamsters fed beef tallow than those fed corn oil diets. Carcinoma in situ multiplicity was elevated in hamsters fed high-fat diets irrespective of the nature of fat fed. Pancreatic adenocarcinoma multiplicity was elevated in hamsters fed the low- or high-beef tallow diets compared with the low- or high-corn oil diets. The mixture of fat resulted in an intermediate yield.     

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 intervention during the postdosing phase of L-azaserine-induced preneoplastic lesions

The effects of intervention by diets with high or low levels of dietary fat on the development of preneoplastic pancreatic lesions were examined. Wistar rats were treated ip at 14 days of age with a 30-mg/kg dose of L-azaserine [CAS: 115-02-6; diazoacetate serine (ester)] and weaned onto the test diets. Animals fed 5% corn oil had fewer preneoplastic lesions compared to animals fed 20% corn oil throughout the 4-month posttreatment period. The strong response observed in rats fed 20% corn oil could be markedly reduced by intervention with a 5% corn oil diet halfway through the posttreatment period. Similarly, the low response in animals fed 5% corn oil could be markedly elevated by intervention with a high-fat diet. These results provide evidence for the hypothesis that tumor development may be modified by dietary means.     

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.     

Effect of different levels of dietary trans fat or corn oil on azoxymethane-induced colon carcinogenesis in F344 rats

The effect of various levels of dietary corn oil or trans fat on azoxymethane (AOM; CAS: 25843-45-2)-induced carcinogenesis was investigated in female F344 rats fed the AIN-76 semipurified diets. Starting at 5 weeks of age, groups of rats were fed the low-fat diet containing 5% corn oil (designated as low-fat control diet). At 7 weeks of age, all animals except the vehicle-treated controls, were given sc injections of AOM (15 mg/kg body wt, once weekly) for 3 weeks. After 1 week, groups of animals were transferred to semipurified diets containing 13.6% corn oil and 23.5% corn oil or high-fat diets containing 5.9% corn oil plus 5.9% trans fat plus 11.8% Oleinate (low trans fat), 5.9% corn oil plus 11.8% trans fat plus 5.9% Oleinate (intermediate trans fat), and 5.9% corn oil plus 17.6% trans fat (high trans fat). Fecal bile acids were measured in vehicle-treated rats. All animals were necropsied 34 weeks after the last AOM injection. The animals fed the 23.5% corn oil diet had a higher incidence of colon tumors than did those in the groups fed the 5 and 13.6% corn oil diets. There was no difference in colon tumor incidence between the 5 and 13.6% corn oil diet groups. The animals fed the high-fat diets containing low trans fat, intermediate trans fat, and high trans fat developed significantly fewer liver and colon tumors and more small intestinal tumors than did the rats fed 23.5% corn oil diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid was higher in animals fed the 23.5% corn oil diet compared to the excretion in animals fed the other diets.     

Modulation of dietary fat-promoted pancreatic carcinogenesis in rats and hamsters by chronic ethanol ingestion

The effect of chronic ethanol ingestion on dietary fat-promotedpancreatic carcinogenesis was investigated in rats and hamsters.Rats were given a single i.p. injection of 30 mg azaserine perkg body wt at 19 days of age. Hamsters were injected s.c. with20 mg N-nitrosobis(2-oxopropyI)amine (BOP) per kg body wt at6 and 7 weeks of age. The animals were fed a semi-purified diethigh in unsaturated fat (25% corn oil) either separately orin combination with ethanol. Ethanol was provided in drinkingwater at a concentration of 10% (w/v). A separate group maintainedon a diet low in unsaturated fat (5% corn oil) was includedas extra controls. The rats and hamsters were given their dietsand received ethanol via their drinking water after treatmentwith carcinogen. Terminal autopsy of rats was 15 months afterazaserine treatment and of hamsters 12 months after the lastinjection with BOP. Dietary fat was found to enhance pancreaticcarcinogenesis in both rats and hamsters. In rats, ethanol slightlyenhanced the multiplicity but not the incidence of malignanttumours, while in hamsters ethanol did not show any modulatingeffect on dietary fat-promoted carcinogenesis. It was concludedthat dietary fat-promoted pancreatic carcinogenesis as observedin the animal models applied is not significantly modulatedby chronic ethanol ingestion.     

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.     

Relationship between amount and type of dietary fat in promotion of mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene.

Female Sprague-Dawley rats were fed semipurified diets containing various fats, either alone or in combination, to provide different amounts of dietary fat and linoleic acid. One week before commencing the diets, each rat received an intra-gastric dose of the carcinogen 7,12-dimethylbenz[a]anthracene. Rats fed diets containing mixtures of 3% sunflower seed oil and 17% of either tallow or coconut oil developed twice as many tumors as those fed 3% sunflower seed oil or 20% of either saturated fat alone. Tumor yields in the rats fed these mixed-fat diets were comparable to those in rats fed a 20% lard diet, which provided about the same amount of linoleic acid. No further increase in tumor yield was observed in rats fed a 20% sunflower seed oil diet that contained more than five times as much linoleic acid. These results show that a certain amount of polyunsaturated fat, as well as a high level of dietary fat, is required to promote mammary carcinogenesis.     

Effect of dietary fish oil on azoxymethane-induced colon carcinogenesis in male F344 rats

The effect of dietary intake of different levels of Menhaden fish oil on azoxymethane-induced carcinogenesis was examined in male F344 rats fed the semipurified diets. Starting at 5 weeks of age, groups of animals were fed the 5% corn oil (low corn oil) diet. At 7 weeks of age, all animals except the vehicle-treated controls were given s.c. injections of azoxymethane (15 mg/kg body weight/week for 2 weeks). After 4 days, groups of animals were fed the diets containing 4% Menhaden oil + 1% corn oil (low fish oil), 22.5% Menhaden oil + 1% corn oil (high fish oil), 5% corn oil, and 23.5% corn oil (high corn oil). Thirty-four weeks after azoxymethane injections, all animals were necropsied. High fish oil diet had no tumor promoting effect in the large intestine when compared to the high corn oil diet. There was no difference in large intestinal tumor incidence among the other dietary groups. The results of this study indicate that fish oils rich in highly polyunsaturated n-3 fatty acids do not enhance large bowel carcinogenesis and that the fatty acid composition of the dietary fat is one of the determining factors in large bowel carcinogenesis.     

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.     

Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors.

Epidemiological studies suggest that high intake of dietary fat rich in saturated fatty acids increases the colon cancer risk whereas dietary fish oil high in omega-3 fatty acids reduces the colon cancer risk. Previously, we reported that consumption of omega-6 fatty acid rich diets such as corn oil strongly promotes azoxymethane (AOM)-induced colon carcinogenesis in rats as compared to ingestion of a diet with equivalent amount of fat containing fish oil (HFFO) or low-fat diet (LFCO). Expression of PLK3 (Polo-like kinase-3, previously named Prk) is negatively correlated with the development of certain cancers. Ectopic expression of human PLK3 results in cell cycle arrest or induces apoptosis. To understand the role of PLK3 in colon carcinogenesis and to study the effect of types and amount of dietary fat on the expression levels of PLK3 in colon tumors, we analyzed the colon tumors and mucosa of rats administered the diets containing fish oil and corn oil for PLK mRNA expression. Here we report that expression of PLK3 was down-regulated in rat colon tumors. Quantitative polymerase chain reaction demonstrated that PLK3 mRNA levels were significantly lower in carcinogen (azoxymethane)-induced rat colon tumors than their uninvolved normal colonic mucosa. Among the normal mucosa isolated from rats fed on diets with various levels of fat (LFCO, or high fat diet with corn oil, HFCO, or supplemented with fish oil, HFFO), no significant changes in PLK3 mRNA expression was detected. Tumors isolated from rats fed with HFCO diet contained a very low level of PLK3 mRNA expression. Interestingly, tumors from rats fed the HFFO diet did not exhibit as dramatic down-regulation of PLK3 as the tumors of animals fed the HFCO diet. Furthermore, our results also indicate that the ectopic expression of a kinase active PLK3 construct induced apoptosis in HT-29 colon carcinoma cells. These observations suggest for the first time that a decreased activity of PLK3 may play a key role in colon tumor development as well as in HFCO-induced colon tumorigenesis.     

Effect of different levels of omega-3 and omega-6 fatty acids on azoxymethane-induced colon carcinogenesis in F344 rats

The effect of various levels of dietary Menhaden fish oil containing omega-3 fatty acids plus corn oil containing omega-6 fatty acids fed during the postinitiation phase of colon carcinogenesis was studied in male F344 rats. Starting at 5 weeks of age, groups of animals were fed the 5% corn oil (5% CO) diet. At 7 weeks of age, all animals except the vehicle-treated controls were administered s.c. injections of azoxymethane (15 mg/kg body wt/week for 2 weeks). 4 days after carcinogen or vehicle treatment, groups of animals were transferred to experimental diets containing 4% Menhaden oil + 1% corn oil (4% MO + 1% CO), 23.5% corn oil (23.5% CO), 17.6% corn oil + 5.9% Menhaden oil (17.6% CO + 5.9% MO), 11.8% corn oil + 11.8% Menhaden oil (11.8% CO + 11.8% MO), or 5.9% corn oil + 17.6% Menhaden oil (5.9% CO + 17.6% MO) and fed these diets until termination of the experiment at Week 38 after carcinogen treatment. An additional group consuming a 5% CO diet was continued on these diets. Colon mucosal ornithine decarboxylase activity and microsomal fatty acid composition of colon mucosa were measured in vehicle-treated animals fed experimental diets for 14 weeks. Fatty acids were also analyzed in the microsomal fraction of colon tumors at termination of the experiment. The body weights of animals fed various experimental diets were comparable. Feeding of high fat diets containing 17.6% CO + 5.9% MO, 11.8% CO + 11.8% MO, or 5.9% CO + 17.6% MO significantly inhibited the incidence (percentage of animals with tumors) of colon adenocarcinomas compared to that of 23.5% CO diet. However, the multiplicity (number of tumors/rat) of colon adenocarcinomas was significantly inhibited only in groups fed the 5.9% CO + 17.6% MO compared to those fed the 23.5% CO diet. The incidence and multiplicity of adenocarcinomas were greater in animals fed the 23.5% CO diet compared to those fed the 5% CO diet. Colonic mucosal ornithine decarboxylase activity was lower in animals fed the 11.8% CO + 11.8% MO, 5.9% CO + 17.6% MO, 5% CO, and 4% MO + 1% CO diets compared to the levels in animals fed the 23.5% CO diet. The increasing levels of Menhaden oil in the diet significantly increased the omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid and decreased the omega-6 fatty acids such as linoleic acid, linolenic acid, and arachidonic acid in microsomal fractions from colonic mucosa and tumors.     

Similarity between trans fat and saturated fat in the modification of rat mammary carcinogenesis

Commercial hydrogenation of vegetable oils results in the introduction of trans fatty acids. In the present study, we have investigated the effect of feeding a fat which contained approximately 38% trans isomers (designated trans fat) on the induction of mammary tumors by dimethylbenz(a)anthracene in rats. The corresponding control fat (designated cis fat), which had a similar fatty acid composition, consisted of only cis isomers. Since both the trans and cis fats were rather saturated, a comparison was also made between these 2 types of fat and corn oil, which contains about 60% linoleic acid (C18:2). Each fat was present in the diet at 2 levels, 5 and 20% by weight. Although rats fed the 20% trans fat or cis fat diets had a slightly higher tumor incidence and yield than did those on the corresponding 5% fat control diets, the difference was not statistically significant. In contrast, rats fed the 20% corn oil diet developed a much greater number of tumors than did rats fed a diet containing only 5% corn oil. Further analysis of the data showed that diets containing either trans fat or cis fat were much less effective than were the corn oil diets in promoting the development of mammary neoplasia at either the 5 or 20% level. Our results thus suggest that trans fat behaves very much like a saturated fat in the modification of mammary tumorigenesis. A determination of the fatty acid content of the mammary fat pad indicated that its composition generally reflected the dietary fatty acid intake, with the incorporation of trans isomers into the mammary tissue found to be dependent on the quantity of trans fat in the diet.     

Enhancement of pancreatic carcinogenesis in hamsters fed a high-fat diet ad libitum and at a controlled calorie intake

An enhancement of pancreatic cancer induced by N-nitrosobis-(2-oxopropyl)amine (BOP) was reported previously in Syrian hamsters fed high-fat diet following carcinogen treatment. The purpose of our research was to determine if this enhancement was due to the consumption of more calories by the hamsters fed the high-fat diet. Male hamsters were treated with a single injection of BOP (20 mg/kg body weight s.c.) at 8 weeks of age. One week later they started either on a low-fat diet (4.3% corn oil) or a high-fat diet (20.5% corn oil) that was fed until the end of the experiment at 92 weeks after BOP. Diets were fed either ad libitum or in a control-fed protocol. The control-fed groups had equivalent calorie intakes and were restricted slightly in comparison with the ad libitum-fed hamsters. BOP treatment reduced survival slightly but survival did not differ significantly in accordance with dietary assignment. Body weight was elevated in the hamsters fed high-fat diet ad libitum in comparison with those fed low-fat diet ad libitum. However, differences were not observed in hamsters fed low- and high-fat diets by the control-fed protocol. Pancreatic carcinogenesis was enhanced about 3- to 4-fold when hamsters were fed high-fat diet by either protocol. The degree of enhancement did not differ with the feeding regimen. However, the higher death rate with pancreatic cancer occurred earlier in the ad libitum-fed hamsters than in the control-fed hamsters.     

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.