A comparison of the effects of the prostaglandin synthesis inhibitors indomethacin and carprofen on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats fed different amounts of essential fatty acid

The effects of the cyclooxygenase inhibitors indomethacin and carprofen on the enhancement of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis by dietary linoleate have been compared in female Sprague-Dawley rats. Indomethacin and carprofen, 0.004% and 0.02% (w/w) in the diet, respectively, were fed to rats receiving 20% fat diets containing 0.5, 4 or 12% linoleate starting 7 days after administration of 5 mg DMBA i.g. Indomethacin was shown to have a marked inhibitory effect on mammary tumorigenesis in rats fed the 4 and 12% linoleate diets, but did not alter tumorigenesis in rats fed the 0.5% linoleate diet. In contrast, carprofen was not inhibitory in any of these dietary groups, or in a separate experiment in which a 5% fat--3% linoleate diet was fed. The effect of each drug on prostaglandin E2 (PGE2) levels in normal mammary glands enriched in epithelial cells after a 3-week pretreatment with 17 beta-estradiol and progesterone was also investigated. Carprofen was shown to reduce PGE2 levels to a similar or greater extent than indomethacin at each level of linoleate in the diet. These data demonstrate that a reduction in PGE2 synthesis in the mammary epithelium does not correlate with inhibition of mammary tumorigenesis, and that other factors, including possible alterations in other products of the arachidonic acid cascade, are responsible for this inhibitory effect.     

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.     

Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylornithine with piroxicam or fish oil

An inhibitor of ornithine decarboxylase, difluoromethylornithine (DFMO), and two inhibitors of prostaglandin biosynthesis, piroxicam and menhaden fish oil, were examined for their effect on intestinal tumorigenesis in male Sprague-Dawley rats fed a 5% fat semisynthetic diet. Each agent was given individually in one of two doses as follows: DFMO, 0.05% and 0.1% in the drinking water; piroxicam, 65 mg/kg diet and 130 mg/kg diet; and menhaden fish oil, 1.25% and 2.50% of the diet. Additional animal groups were given combinations of the lower dose of DFMO and the lower dose of either piroxicam or fish oil. Intestinal tumors were induced by sc injections of azoxymethane (AOM; CAS: 25843-45-2) at 8 mg/kg (body wt) weekly for 8 weeks. Test diets were started 1 week prior to the first dose of AOM, and the rats were sacrificed 26 weeks later. Rats that received either dose of DFMO or the high dose of piroxicam developed significantly fewer intestinal tumors compared to controls. The low dose of piroxicam and the fish oil given at either dose level had no effect. The combination of the low dose of DFMO and the low dose of piroxicam reduced tumor formation more than either dose of DFMO alone, whereas the low dose of DFMO and fish oil together was no more effective than either dose of DFMO alone. These results show that a combination of a small amount of DFMO and piroxicam, each acting through a different mechanism, exerts an additive inhibitory effect on intestinal tumor formation in rats.     

Effect of n-3 and n-6 fatty acids on 7,12 dimethylbenz (a) anthracene-induced mammary tumorigenesis

Numerous studies have consistently shown that vegetable oils containing linoleic acid enhance mammary tumorigenesis more effectively than fish oils containing eicosapentaenoic and docohexaenoic acids. The purpose of this investigation was to study these and additional n-3 and n-6 PUFA, e.g., a-linolenic (a-LN) (18:3 n-3) and gamma-linolenic (GLA) (18:3 n-6) acid. Different oils were used as dietary sources of fatty acids: corn (CO) (61% LA); blackcurrant (BCO) (44% LA, 18% GLA and 16% a-LN); fish oil (FO) (mixed with corn oil, 12% LA and 24% EPA + DPA + DHA). Thirty-five-day-old female Sprague-Dawley rats were divided into 5 dietary treatment groups and were allowed to feed ab libitum on one of the test diets: I. BCO (23.5%); II. CO (23.5%); III. BCO (15.5%) + FO (8%); IV. FO (20.5%) + CO (3%); and V. BCO (20.5%) + FO (3%). From 48 to 52 days of age, rats in all five groups were fed rat chow. At 50 days of age, all rats were given 5 mg DMBA by oral intubation, and 2 days later the test diets were resumed until termination of the experiment. Analysis of tumor incidence, and multiplicity data for 5 diet groups indicated that rats fed 23.5% CO (II) exhibited enhanced mammary tumor yields when compared to animals on the remaining 4 diets in the order II greater than I, III, V greater than IV. Since the level of fat (23.5% w/w) was similar in all 5 diets, and body weight gain was in the order IV greater than II greater than I, the results of this study indicate that differences in tumor yields were related to fatty acid composition of diets. In support of this conclusion, fatty acid profiles of RBC and tumor phosphoglycerides reflected dietary fatty acid composition. In groups I and II, even though tumor levels of LA were similar, the levels of GLA, DHLA (20:3 n-6) and a-LN were higher in I compared to II, suggesting that these differences may be associated with lower yields of DMBA-induced mammary tumors in group I. Incorporation of marine type n-3 PUFA (EPA, DPA and DHA) in tumor PL was greater in Group IV compared to plant type n-3 PUFA (a-LN) in Groups I, III, and V. Since tumor yields were the lowest in Group IV, these results suggest that incorporation of marine type n-3 PUFA into cell membranes does not favor development of DMBA-induced mammary tumors.     

Effect of dietary menhaden oil on tumor cell loss and the accumulation of mass of a transplantable mammary adenocarcinoma in BALB/c mice

A reduction in the size of transplantable mammary adenocarcinoma IX was achieved when female BALB/c mice were fed isocaloric 10% fat diets containing either hydrogenated cottonseed oil (HCTO) or menhaden oil (MO) as opposed to those mice fed corn oil (CO). Indeed, CO increased the size of the neoplasms when fed alone at 5 or 1% of the diet, although such diets contained less fat calories than did the 10% fat diets containing the other two oils. At the 10% level of dietary fat, enhanced accumulation of tumor mass was observed even when 7.5, 5.0, and 2.5% CO was administered in combination with either HCTO or MO. Although this effect of CO could not be inhibited when nine times as much HCTO was added to the diet, such growth enhancement was abolished when the diet contained nine times as much MO. Hence these experiments emphasized the importance of the type rather than the amount of dietary fat. Whereas MO contained polyunsaturated fatty acids (PUFA's) [approximately 1% as linoleic acid, approximately 16% as 5,8,11,14,17-eicosapentaenoic acid (EPA), approximately 11% as 4,7,10,13,16,19-docosahexaenoic acid (DHA)], HCTO contained none and CO had about 60% of its constituent fatty acids in the form of linoleic acid. The rate of tumor cell loss, determined by the [125I]5-iodo-2'-deoxyuridine method, in the 10% MO-fed or the 10% HCTO-fed mice (54 or 45%, respectively) was more than twice that observed for tumors from the 10% CO-fed mice (22%). These observations were discussed in terms of the influence of the dietary PUFA linoleic acid [C 18:2 (No. of carbons:No. of double bonds), n-6], the PUFA EPA (C 20:5, n-3), and the PUFA DHA (C 22:6, n-3) on the size of mammary tumors and on the involvement of prostaglandins in this process.     

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.     

Effect of the prostaglandin synthetase inhibitor indomethacin on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats fed different levels of fat

The effect of the prostaglandin synthetase inhibitor indomethacin on the dietary fat enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis has been examined in female Sprague-Dawley rats. Rats were fed either a normal-fat or high-fat diet (5 or 18% corn oil, respectively) with or without 0.004% indomethacin, starting 3 days after a single intragastric intubation of 5 mg 7,12-dimethylbenz(a)anthracene. Results of this experiment demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as measured by a decreased tumor incidence, a decreased number of tumors per group, a decreased tumor size, and an increased latency. No effect of indomethacin was observed in rats fed the normal-fat diet. These data suggest that at least part of the stimulatory effect of polyunsaturated fat on 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis may be mediated through an increased synthesis of prostaglandins.     

Effects of dietary fat on hepatic microsomal and cytosolic mutagenic activation of 2-aminofluorene.

The present study was designed to examine the effects of different high fat diets on the liver microsomal and cytosolic mutagenic activation of 2-aminofluorene. Male Sprague-Dawley rats were fed either a low fat (5% corn oil) or high fat (20%) diets containing either corn oil (CO), menhaden oil (MO) or beef tallow (BT). After 2 weeks on the test diets, animals from each group were placed on a protocol of weekly injection with 1,2-dimethylhydrazine dihydrochloride (DMH) for 10 weeks. Animals were given DMH injections i.p. and killed 3 h after injection following 5 and 10 DMH treatments. The metabolic activity of liver microsomes and cytosol was assessed by the Ames test using 2-aminofluorene as a standard mutagen. Beef tallow-fed rats had the highest microsomal mutagenic activation, followed by the basal diet. Decreased liver microsomal and cytosolic metabolism of the reference mutagen was detected in the MO and CO diets compared to basal or BT diets. However, there was an increased activity in MO and CO fed groups after week 10, while beef tallow showed a slightly decreased activation. These data indicate that type of dietary fat affects liver microsomal mutagenic activation of carcinogens.     

Failure of indomethacin to inhibit growth of the R3230AC mammary tumor in rats

The relationship between the dietary lipid-induced growth of the R3230AC mammary tumor and prostaglandin E2 (PGE2) levels as well as the effect of the prostaglandin synthetase inhibitor indomethacin (Ind) on these parameters was examined. F344 rats fed a high-fat (HF) diet containing 20% corn oil demonstrated more rapid tumor growth and higher tumor and plasma PGE2 levels than rats fed a 20% hydrogenated cottonseed oil (HCTO) diet. Addition of 0.004% Ind to the HF diet markedly reduced tumor and plasma PGE2 levels. However, Ind had no effect on tumor growth. Neither the fatty acid composition nor the insulin-binding capacity of the tumor plasma membranes was affected by Ind. Membranes from animals fed HF diets with or without Ind bound more 125I-labeled insulin than membranes from HCTO-fed rats. The results suggest that, for the R3230AC mammary tumor, reduction in both tumor and plasma PGE2 levels by Ind did not result in reduced tumor growth in animals fed diets high in polyunsaturated fatty acids.     

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.     

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.     

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.     

Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors

Studies in laboratory animals and epidemiological surveys suggest a relationship between the type and amount of dietary fat and mammary cancer. One mechanism proposed to explain this relationship is modulation by dietary fat, of mammary tumor eicosanoid levels through action at the rate limiting enzyme in eicosanoid synthesis, cyclooxygenase (COX). Until recently there have been no studies which have examined COX gene expression in human breast or rodent mammary tissues. In this study we have demonstrated the presence of two immunoreactive isoforms of cyclooxygenase (COX-1 and -2), and the modulating effects of n-3 fatty acids on their expression, in N-nitrosomethylurea (NMU)-induced rat mammary tumors. Three different high fat diets were compared namely, corn oil (CO) 23%; CO 18% menhaden oil (MO) 5%; CO, 5%/MO 18%; low fat corn oil (5%) served as a control. It was found that immunoreactive COX-2 protein levels were approximately 3x higher than COX-1 levels in NMU-induced mammary tumors. Moreover, the high menhaden oil diet (rich in n-3 fatty acids) significantly suppressed both COX-1 (-28%) and COX-2 (-36%) protein levels when compared to the high corn oil diet. No differences were found among the other treatment groups when compared pair-wise or with low-fat control. The mechanism(s) by which n-3 fatty acids suppress COX-1 and COX-2 remain to be determined.     

Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene

Female Sprague-Dawley rats, 50 days of age, were treated with a single dose of 5 mg of 7,12-dimethylbenz(a)anthracene intragastrically. 3 days after carcinogen treatment, the rats were put on semisynthetic diets containing 20% by weight of corn oil (CO), soybean oil (SBO), crude palm oil (CPO), refined, bleached, deodorized palm oil (RBD PO) and metabisulfite-treated palm oil (MCPO) for 5 months. During the course of experiments, rats fed on different dietary fats had similar rate of growth. Rats fed 20% CO or SBO diet have higher tumor incidence than rats fed on palm oil (PO) diets; however differences of mean tumor latency periods among the groups were not statistically significant. At autopsy, rats fed on high CO or SBO diets had significantly more tumors than rats fed on the three PO diets. Our results showed that high PO diets did not promote chemically induced mammary tumorigenesis in female rats when compared to high CO or SBO diets. CO and SBO differ greatly from the palm oils in their contents of tocopherols, tocotrienols, and carotenes. But further experiments would be required to determine whether the observed differences in tumor incidence and tumor numbers were due to the differences in these minor components or due to the unique triglyceride structure of the palm oils. Analysis of the fatty acid profiles of plasma total lipids of tumor-bearing rats and of the tumor total lipids showed that, with the exception of arachidonic acid, the fatty acid profiles reflect the nature of the dietary fats. At autopsy, there were no differences in the plasma total cholesterol contents among rats fed on different dietary fats, but rats fed on palm oil diets had a significantly higher plasma triglyceride level than that of rats fed CO or SBO diets. As for the tumor lipids, there were no significant differences in the triglyceride, diglyceride, and phospholipid levels when the CO or SBO groups were compared to the palm oil groups.     

II. Effect of n-3 and n-6 fatty acids on mammary H-ras expression and PGE2 levels in DMBA-treated rats

In an attempt to evaluate some of the mechanisms by which dietary n-3 and n-6 PUFA influence 7,12,dimethylbenz(a)anthracene (DMBA)-induced mammary tumorigenesis, we measured: 1) concentrations of prostaglandin (PG) E1 (metabolite of C20:3, n-6) and PGE2 (metabolite of C20:4, n-6); and, 2) expression of H-ras oncogene in non-cancerous (NC) and cancerous (C) mammary tissues taken from rats 14 weeks after they were treated with 5 mg DMBA. Five groups of rats were fed one of the synthetic diets containing 23.5% of fat by weight: I. Blackcurrant oil (BCO) (23.5%); II. corn oil (CO) (23.5%); III. BCO (15.5%) + fish oil (FO) (8%); IV. FO (20.5%) + CO (3%); and V. BCO (20.5%) + FO (3%). PGE1 and PGE2 levels were lower in NC mammary tissues than in corresponding C tissues in all 5 diet groups. In Group IV, PGE2 levels in both NC and C tissues were significantly lower than in those of the remaining 4 groups. In groups fed BCO alone (I) or in combination with FO (III and V), PGE2, content in C tissue was lower compared with the corn oil-fed group (II), but these observations were significant only for III and V. Conversely, in Groups III and V, the content of PGE1 in C tissues was significantly higher. The results of the present study demonstrate interactions and competition between 3 eicosapolyenoic acids that act as substrates for cyclooxygenase. The observation that PGE2 production is reduced when mammary tumor development was inhibited confirms earlier findings. Whether these changes in eicosanoids can explain differences in ras p21 levels as judged by cross-linking to a-32 P-GTP remains to be investigated in greater detail. Preliminary results from a small number of samples indicate that expression of H-ras in C mammary tissue was in the order CO (II) greater than BCO (I) = FO (IV).     

Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet

The effects of indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor content of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma have been examined in female Sprague-Dawley rats. The rats were fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet with or without 0.005% indomethacin starting 7 days after intragastric administration of a single dose of 5 mg 7,12-dimethylbenz(a)anthracene. The results demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased tumor incidence, a decreased number of tumors per group, and an increased latency. Contrary to what had been expected, however, indomethacin promoted tumor proliferation in both the high- and low-fat diet groups, as evidenced by an increased tumor size, an increased bromodeoxyuridine-labeling index, and a decreased potential tumor-doubling time. No significant difference in either the estrogen receptor or progesterone receptor content of the tumor was noted. It can be concluded, therefore, that indomethacin significantly reduced tumorigenesis in the high-fat diet group but significantly promoted tumor proliferation in both the high- and low-fat diet groups.     

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.     

Lack of a protective effect of menhaden oil on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate

Fish oil has been shown to have a protective effect in some cancer models. To determine whether fish oil alters skin tumorigenesis, a study was designed using the initiation-promotion mouse skin carcinogenesis model, feeding mice during the promotion stage a constant overall amount of dietary fat (10%) in which the levels of menhaden oil (MO) varied from 0 to 8.5% or corn oil (CO) at 10%. SENCAR mice were initiated with 10 nmol dimethylbenz[a]anthracene. Two weeks later mice were divided into five groups and maintained on one of the following AIN-76 based diets consisting of: 8.5% coconut oil (CT)/1.5% CO (diet A); 1% MO/7.5% CT/1.5% CO (diet B); 4% MO/4.5% CT/1.5% CO (diet C); 8.5% MO/1.5% CO (diet D); or 10% CO (diet E). Two weeks later, promotion with twice weekly applications of 1 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) was begun and continued for 24 weeks. No statistically significant differences in kcal food consumed or body wts were observed between diet groups during the study. The final papilloma and carcinoma incidence was not different among the diet groups. However, differences were seen in the rate of papilloma appearance with the group fed diet E (10% CO) being the slowest and diet B being the most rapid. In a parallel study, ornithine decarboxylase activity, a suggested marker of promotion, was greatly elevated in the epidermis of all TPA-treated mice and the effect of diet tended to reflect the different rates of tumor formation observed among the groups. These data indicate that the diets containing fish oil were not protective in the final incidence of tumor formation and suggest that a better understanding of the complex interactions is warranted before recommendations are made to alter the human diet for cancer prevention.     

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.