Selenium-enriched garlic inhibits the early stage but not the late stage of mammary carcinogenesis

Previous work has shown that the efficacy of cancer preventionby selenium-enriched garlic (Se-garlic) is primarily dependenton the action of selenium. Additionally, supplementation ofSe-garlic inhibited the post-initiation phase of mammary carcinogenesiswhen it was given continuously to the animals. In this report,experiments were carried out in which treatment with the Se-garlicwas started after carcinogen dosing (DMBA or MNU) but was restrictedto either the early or late stage of neoplastic progression.The results from these two models showed that a short-term exposureto the Se-garlic for 1 month immediately following carcinogenadministration was just as effective in cancer prevention asthe continuous exposure regimen (5 months), suggesting thatthe Se-garlic may irreversibly alter the process of clonal expansionand/or selection of transformed cells during their early stageof development. Plasma and mammary tissue selenium levels essentiallyreturned to basal levels at 1 month after withdrawal of supplementation.These observations imply that the outcome of cancer protectionby short-term Se-garlic intervention was not due to a slow turnover,and therefore a lingering presence, of selenium in the targetorgan or in the circulation. The above finding was in contrastto that of a second study in which Se-garlic was supplementedstarting at 13 weeks after carcinogen treatment With this protocol,the number of new tumors and the number of new tumor-bearingrats found during the intervention period (weeks 13 to 22) werenot statistically different between the control and supplementedgroups, suggesting that Se-garlic had a minimal effect on thelater stages of mammary carcinogenesis.     

Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats

The protective effect of progesterone or tamoxifen, an antiestrogenic agent, was investigated in estrogen-induced mammary carcinogenesis. Multiple mammary tumors (MT) of tubular or medullary carcinoma type developed at a high rate following prolonged treatment of ovariectomized W/Fu rats with diethylstilbestrol or 17 beta-estradiol. All MTs were located adjacent to the nipple and were slow-growing. The induction rate, multiplicity and size of estrogen-induced MTs were reduced by the simultaneous administration of either progesterone or tamoxifen. The estrogen-induced pituitary tumorigenesis was effectively inhibited by tamoxifen treatment, but it was not affected by progesterone. The results indicated that the inhibitory effect of progesterone or tamoxifen in estrogen-induced carcinogenesis is attributable to interference with the binding of estrogen to the estrogen receptors on the target cells.     

Choline enhances acetylaminofluorene promotion of liver carcinogenesis in female but not in male rats.

The growth of focal lesions during chemical carcinogenesis has been analyzed after promotion in the liver of female and male rats receiving choline for 4 or 5 weeks. The number and size of foci of altered hepatocytes were first evaluated after methylnitrosourea was used as initiator and 2-acetylaminofluorene (2-AAF) associated with carbon tetrachloride as promoter. The development of enzyme-altered foci was lower in female rats than in males. Choline given intragastrically stimulated the growth of focal lesions in female rats by increasing both the enzyme-positive area of the single focus and the total area of positive foci per cm2 of liver section up to levels close to those of males. No effect of choline was observed in males. In a second set of experiments, focal proliferative lesions induced with the Solt-Farber model were larger in females fed a choline-enriched diet during the promotion phase, as a result of the area of the focus and the total area of foci per cm2 of liver being higher than that in females not receiving choline, with no significant change in the number of foci. When cell proliferation was selected during promotion by 2-AAF and carbon tetrachloride instead of partial hepatectomy, the effect of the choline-enriched diet was even more pronounced. This difference might be accounted for by the greater hepatotoxicity of xenobiotics after choline administration. The hypothesis that choline may enhanced hepatocyte susceptibility towards 2-AAF action by an increase in drug toxicity is discussed.     

Sialic acid metabolism in rats undergoing chemically-induced mammary gland carcinogenesis in specific dietary states.

The enzymes responsible for the activation, transfer and hydrolysis of sialic acids were investigated in female rats with mammary adenocarcinomas induced by administration of a single oral dose (10 mg) of 7,12-dimethylbenz[alpha]anthracene. The carcinogenic process was modulated by the levels and degree of unsaturation of the dietary lipids. Tumor incidence was highest in rats fed a diet containing 20% corn oil, intermediate with 18% coconut oil plus 2% linoleic acid, and lowest in the group receiving a diet with 2% linoleic acid. Sialyltransferase and CMP-N-acetylneuraminic acid synthetase activities were higher in tumors than in control mammary glands. Neuraminidase activity, on the other hand, was higher in control tissue than in tumors. In addition to these tumor-related effects, comparison of the enzyme levels in mammary tissues from control animals of the 3 dietary groups revealed the presence of diet-related effects on sialic acid metabolism. In the livers of tumor-bearing rats, only minor changes of enzyme activities were detected.     

Effect of chronic dietary ethanol consumption on the initiation and promotion of chemically-induced esophageal carcinogenesis in experimental rats

Preliminary dose finding studies showed that 22 mg/kg of N-nitrosomethylbenzylamine(NMB_zA) delivered over 5 days did not induce esophageal lesions,but 18 mg/kg administered over a period of 2 or 3 weeks didinduce these lesions. Based on these results, Sprague—Dawleyrats were treated with 2.5 mg/kg NMB_zA three times a week for3 weeks to initiate esophageal carcinogenesis. The experimentalanimals were administered isocaloric ethanol diet either beforeand during NMB_zA initiated carcinogenesis, or after initiationas a tumor promoter. The esophagi of rats that died or who wereterminated at 18 months of age were examined for nodules andtumors. When ethanol was administered before and during initiation,the mean frequency of esophageal lesions was 8.04 ± 3.04/ratwith an average size of 1.44 ± 0.27mm versus 12.41 ±2.12/rat and 0.92 ± 0.17 mm respectively for the controls.Only three out of 13 of the ethanol-fed rats had tumors (mainlysquamous papillomas) versus 10 out of 26 of the control-fedanimals. Ethanol consumption before and during initiation, therefore,decreased the incidence of esophageal nodules and tumors. Withethanol administered as a promoter, on the other hand, whileincidence of the total lesions was not affected appreciably,the incidence of tumors was remarkably increased. With ethanolpromotion the mean frequency of lesions was 8.75 ± 1.07/ratwith an average size of 1.02 ± 0.09 mm versus 10.94 ±1.49/rat and 1.32 ± 0.13 mm respectively for the controls.In this case, the ethanol-consuming rats had tumors in 14 outof 75 animals versus one small tumor in 32 of the controls.The results indicate that the occurrence of esophageal tumorsis inhibited by simultaneous ethanol administration, but promotedwhen ethanol is administered post-initiation ostensibly by allowingextensive dysplastic proliferation of the carcinogen-inducedlesions.     

Prolonged effects of beta-estradiol 3-benzoate on thyroid tumorigenesis in gonadectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine

The prolonged modulatory effects of beta-estradiol 3-benzoate (EB), a synthetic estrogenic compound, were investigated in a rat two-stage thyroid tumorigenesis model. One week after a single subcutaneous (s.c.) injection of N-bis(2-hydroxypropyl)nitrosamine, gonadectomized F344 rats of both sexes were s.c. implanted with fused pellets containing EB for 32 weeks. Doses of EB at 0, 0.004, 0.02 and 0.1mg were achieved by varying the ratio of EB to cholesterol in the pellet. Major organs including the thyroid, pituitary, liver, kidneys, uterus and brain were weighed and histopathological observation was performed. Serum was assayed for triiodothyronine (T(3)), thyroxine (T(4)) and thyroid-stimulating hormone (TSH). Thyroid weights were increased by the EB pellet implantation in a dose-dependent manner and significantly (P<0.05) elevated in the 0.1mg EB male group and in the 0.02 and 0.1mg EB female groups. The EB treatments dose-dependently suppressed serum T(4) levels and inversely elevated serum TSH levels in both sexes but without statistical significance in females. Histopathologically, EB increased the occurrence of thyroid proliferative lesions in males and showed a tendency for increase in females. Interestingly, the effect of EB was more intensive in males than in females, even the lowest dose inducing a follicular carcinoma in a male. These results, thus indicate the possible contribution of prolonged EB stimulation at lower doses to thyroid tumorigenesis without additional promotive condition.     

Suppression of chemically-induced liver tumors by castration or estradiol-3-benzoate treatment in F344 rats

Epidemiological data reveal that the incidence of liver cancer is markedly higher in men than women. To clarify the mechanism responsible for the induction of higher incidence of liver tumors in male animals, we investigated the modifying effect of sex hormones in diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. F344 male rats (n=120) were divided into two experiments, experiment I (Exp I) and experiment II (Exp II). In each experiment, 60 rats were randomly allocated into four groups. The mini-osmotic pumps containing doses of 47.5 mg (Exp I) or 23.75 mg (Exp II) of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. Animals in group 2 were castrated one week prior to DEN treatment, and animals in groups 3 and 4 were treated with 1 or 10 microg of estradiol-3-benzoate (EB), respectively, one week prior to DEN treatment. Animals in group 1 were treated with DEN alone and sham-operated at the same time. All animals were sacrificed 26 weeks after DEN treatment. In Exp I, liver tumor incidence of group 3 decreased significantly compared with that of group 1 (p<0.05), and tumor multiplicities of groups 2, 3 and 4 were decreased significantly compared to that of group 1 (p<0.01). In Exp II, tumor incidence of group 3 was significantly different (p<0.05) when compared to that of group 1. Immunohistochemical expression of ERalpha was shown in normal appearing cells, but not in tumor cells. Western blot analysis confirmed that ERalpha expression was higher in normal liver tissue compared to tumor tissues. Taken together, we conclude that castration or EB treatment has an inhibitory effect in DEN-induced hepatocarcinogenesis in F344 rats. The reason for ERalpha loss in tumor cells should be further elucidated.     

Anti-carcinogenic activity of d-limonene during the initiation and promotion/progression stages of DMBA-induced rat mammary carcinogenesis

d-Limonene was found to be effective in reducing the averagenumber of rat mammary carcinomas that developed in 7,12-dimeihylbenz[a]anthracene-treatedrats when the terpene was fed during the initiation or duringthe promotion/progression stage of carcinogenesis. The timeto the appearance of the first tumor was extended only whend-limonene was fed during the initiation stage. These effectscould not be attributed to changes in mammary-relevant endocrinefunctions.     

Post-initiation treatment of Indole-3-carbinol did not suppress N-methyl-N-nitrosourea induced mammary carcinogenesis in rats.

The consumption of cruciferous vegetables (the Family of Cruciferae) such as cabbage, broccoli and Brussels sprouts has been shown to have cancer chemopreventive effects in humans and experimental animals. Indole-3-carbinol (I3C), one component of cruciferous vegetables, has been shown to exert cancer chemopreventive influence in liver, colon, and mammary tissue when given before or concurrent with exposure to a carcinogen. However in some reports, there has been evidence that consumption of I3C after carcinogen treatment might be associated with tumor promotion in some tissues. There have been no reports, to our knowledge, of post-initiation effects of I3C in the N-methyl-N-nitrosourea (MNU)-induced mammary tumor model in rats. Our studies were performed to examine this question. Ninety-six, 4-week-old female Sprague-Dawley rats were randomly divided into five groups. The animals of groups 1, 2 and 3 received an intraperitoneal injection of MNU at the age of 50 days. The animals of groups 4 and 5 were injected with saline only at the same time. Animals of groups 1 and 2 were given diet containing 100 ppm and 300 ppm I3C from week 1 until week 25 after MNU treatment. The animals of group 4 were given basal diet containing 300 ppm I3C without MNU treatment. All animals were killed at week 25. The incidences of mammary tumors in the groups 1, 2 and 3 were 95.8% (23/24), 83.3% (20/24) and 82.4% (28/34), respectively. The average number of tumors in the tumor bearing rats of the MNU and I3C 300 ppm group (group 2; 3.85+/-0.63) was higher than that in the MNU alone group (group 3; 2.46+/-0.31). These results represented that exposure to I3C after carcinogen treatment did not suppress development of mammary tumors.     

Promotion,but not progression,effects of tamoxifen on uterine carcinogenesis in mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine

Effects of tamoxifen (TAM) on development of uterine endometrial carcinogenesis were studied in intact and ovariectomized (OVX) mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). In experiment I, animals were implanted with cholesterol (ChL, controls) or TAM (5% w/w) and/or 17beta-oestradiol (E(2), 0.5% w/w) pellets s.c. from 9 to 25 weeks of age, until the termination of the experiment, and all received a single intra-uterine administration of ENNG (12.5 mg/kg) at 10 weeks of age. They were divided into four groups: ENNG + ChL (control), ENNG + TAM, ENNG + E(2) and ENNG + TAM + E(2). Endometrial proliferative lesions (hyperplasias and/or carcinomas) were observed in all groups, the incidences in the TAM- and/or E(2)-treated groups being two times higher than in the ChL-treated control animals. High induction (11/20, 55%) of adenocarcinomas was observed in the E(2) group but this was significantly decreased in combination with TAM (2/20, 10%), no carcinomas being found in the TAM group. In experiment II, animals pre-treated with TAM (10 weeks) and receiving E(2) post-treated (4 weeks) developed adenocarcinomas, although no cancers were observed in mice treated by ChL instead of TAM. In animals pre-treated with TAM and post-treated with ChL or TAM, no adenocarcinomas were also developed. In OVX mice (experiment III), proliferative lesions were observed in the TAM- and/or E(2)-treated groups, at incidences significantly higher than in ChL-treated animals, in which these lesions were completely absent. However, no adenocarcinomas were found, only slight hyperplasias being observed in the TAM group, although the incidence of adenocarcinoma was highest in the E(2) alone group, and significantly decreased in combination with TAM, as in experiment I. These results indicate that TAM may itself exert promotion effects, while exhibiting an anti-progression influence on uterine carcinogenesis in adult mice initiated by ENNG and receiving E(2).     

Interferon-alpha/beta in virus-induced mouse mammary carcinogenesis: effects on the spontaneous process and on the progression of transplanted pre-neoplastic lesions.

Low levels of anti-viral activity, mainly interferon alpha/beta (IFN-alpha/beta), are regularly found in lymphoid tissues of BALB/c mice infected with the C3H strain of mammary tumor virus. At the time of tumor development, significant amounts of anti-viral activity were detected in homogenates of spleen and mammary tumors, but not in blood and normal mammary glands. This activity is pH2-resistant and neutralized by antibody to IFN/alpha-beta. The pathogenetic role of IFN in mammary carcinogenesis was investigated in 2 ways: (a) by treating virus-infected newborn mice with antibody to IFN-alpha/beta, and (b) by giving either the latter antibody or IFN-alpha/beta to virus-free animals transplanted with pre-neoplastic lesions. Mice were treated only for 2 months, starting either 1 week after birth or immediately after tumor transplant. In case (a), treatment with antibody to IFN-alpha/beta shortened the incubation period of mammary carcinomas and decreased the mean survival time. In case (b), anti-IFN antibody did not significantly affect the development of mammary tumors. However, exogenous IFN-alpha/beta markedly reduced both tumor incidence and mortality rate. These results indicate that endogenous IFN-alpha/beta plays a crucial role in the in vivo restriction of the early infectious phase of spontaneous carcinogenesis and that relatively high doses of IFN-alpha/beta may inhibit the progression of pre-neoplastic lesions.     

Time-dependent promotion activity of 17beta-estradiol on uterine carcinogenesis in mice initiated with N-ethyl-N-nitrosourea

The time-dependent promotion activity of 17beta-estradiol (E2) by initiation with N-ethyl-N-nitrosourea (ENU) on induction of mouse uterine endometrial proliferative lesions was examined. Illumination-induced persistent estrous female CD-1 mice were divided into five groups at 9 weeks of age. At 10 weeks of age, mice in all groups (n=25) were given a single intra-uterine administration of ENU (50 mg/kg), dissolved in polyethylene glycol. Animals in Groups 2 to 5 were then implanted s.c. with an E2 pellet at 9, 11, 14 and 17 weeks of age. The implants were left in place for 8 weeks and then taken out. At the termination of the experiment (week 15 after the ENU-treatment), all surviving mice were killed and the development of uterine proliferative lesions were assessed. All groups demonstrated endometrial hyperplasias and adenocarcinomas and the incidences of the latter in ENU plus E2 treated animals (Groups 2 to 5; 36, 48, 35 and 36%, respectively) were significantly higher compared to 8% for Group 1, without any variation with the age at E2 treatment. However, the incidences of adenocarcinomas plus severe hyperplasias increased from Groups 1 to 5 (28, 40, 56; P<0.05, 61; P<0.05 and 80%; P<0.01, respectively), indicating that promotion effects of E2 on induction of uterine proliferative lesions in the uterine endometrium become more pronounced with the interval after ENU initiation.     

Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays.

We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol (DES)-induced tumor promotion of rat mammary glands initiated with radiation. Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy and were divided into two groups after weaning. In the control group of 39 rats fed a basal diet and then implanted with a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats were fed diet containing 1% curcumin immediately after weaning and received a DES pellet, as for the control. The administration of dietary curcumin significantly reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball's index of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet showed a reduced incidence of the development of both mammary adenocarcinoma and ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment with curcumin, body weight and ovarian weight were reduced, but liver weight was increased. Compared with the control rats, the curcumin-fed rats showed a significant reduction in serum prolactin, whereas estradiol-17beta and progesterone concentrations were not significantly different between the two groups. Curcumin did not have any effect on the concentration of free cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet caused a significant increase in the concentrations of tetrahydrocurcumin, arachidonic acid and eicosapentaenoic acid and a significant decrease in thiobarbituric acid-reactive substance concentration in serum. Whole mounts of the mammary glands showed that curcumin yielded morphologically indistinguishable proliferation and differentiation from the glands of the control rats. These findings suggest that curcumin has a potent preventive activity during the DES-dependent promotion stage of radiation-induced mammary tumorigenesis.     

BCG-modulated mammary carcinogenesis is dependent on the schedule of immunization but is not affected by dietary fat

The present study was designed to study the effect of dietary fat intake on the modulation of dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in rats injected with the methanol extract residue of Bacillus Calmette-Guerin (MER-BCG). Rats were maintained on either a 5% or a 20% corn oil diet for the entire duration of the experiment. When MER-BCG was administered 2 and 3 weeks before DMBA, mammary tumorigenesis was suppressed in the 2 dietary groups with different levels of fat intake. This was in contrast to when MER-BCG was administered 3 and 5 weeks after DMBA; in this case the development of mammary tumors was noticeably enhanced regardless of the fat intake of the host. The magnitude of inhibition or increase by MER-BCG was similar in animals fed either fat level, although a high fat diet consistently stimulated mammary tumorigenesis in the 2 experiments. In vitro assays on T cell mitogen-induced blastogenesis and natural killer cell activity in splenocytes isolated from the untreated rats showed that dietary fat failed to elicit any differential response in these immune functions.     

Dietary effects of conjugated docosahexaenoic acid on N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats

The dietary effects of conjugated docosahexaenoic acid (CDHA) were examined in an N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis model. Female Sprague-Dawley rats were administered 50 mg/kg MNU intraperitoneally at 49 days of age. A powdered AIN-76A diet containing 0, 0.2 or 1.0% CDHA was fed to the rats from 21 to 49 days of age (before MNU; pre-initiation phase) or from 49 days to 40 weeks of age (after MNU; post-initiation phase). Rats were sacrificed when their largest mammary tumor was > or =1 cm in size or when they reached 40 weeks of age. All histologically detected mammary carcinomas were evaluated. In rats that received CDHA after MNU, development of mammary carcinoma > or =1 cm was inhibited, and there was a significant decrease in the final mammary cancer incidence and multiplicity, compared with rats that did not receive CDHA. Consumption of the 0.2% CDHA diet after MNU significantly prolonged latency. Suppression of mammary cancer yield by consumption of a CDHA diet after MNU administration was not dose-dependent. In rats that received CDHA before MNU, suppression of mammary cancer was not observed. These results indicate that CDHA administration in the post-initiation period suppressed mammary carcinogenesis, whereas CDHA administration in the pre-initiation period was ineffective.     

Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue transgenic rats

The major constituents of isoflavones daidzein (DZ) and genistein (GE) interact with the and estrogen receptors in several tissues including mammary tissues. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E(2)) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue transgenic rats. The rats were fed control diet containing the isoflavones and E(2) and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND50. Animals were euthanized at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E(2) supplementation alone resulted in the lac I MFs that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lac I MFs in the mammary tissues of both OVX and INT rats and Hprt MFs in spleen lymphocytes (P < 0.01). In general, feeding the isoflavones or E(2) did not cause any significant changes in DMBA-induced mutagenicity in the mammary tissues. However, feeding the isoflavone mixture (daidzein + genistein; DZG) resulted in a significant reduction in the DMBA-induced lac I MFs (P < 0.05). Cell proliferation as measured by PCNA immunohistochemistry was increased in both OVX and INT rats exposed to DMBA as compared with rats fed control diet (P < 0.05). Mammary histology indicated that hyperplasia was induced in most of the treatment groups including control. Although DMBA did not induce mammary tumors in the OVX rats, adenoma and adenocarcinoma were detected in the mammary glands of INT rats.     

Dietary effects of soy isoflavones daidzein and genistein on 7,12-dimethylbenz[a]anthracene-induced mammary mutagenesis and carcinogenesis in ovariectomized Big Blue transgenic rats

The major constituents of isoflavones, daidzein (DZ) and genistein (GE) are known to interact with the alpha and beta estrogen receptors (ERalpha/beta) in several tissues including mammary. In this study, we used ovariectomy (OVX) to model menopause and determined the effects of DZ, GE or 17beta-estradiol (E2) exposures on chemically induced mutagenesis and carcinogenesis in the mammary glands of female Big Blue (BB) transgenic rats. The rats were fed control diet containing the isoflavones and E2 and treated with a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at PND 50. Animals were sacrificed at 16 or 20 weeks post-carcinogen treatment to assess mutant frequencies (MFs) and histopathological parameters, respectively. The isoflavones or E2 supplementation alone resulted in modest increases in the lacI MF that were not significantly different from the MFs measured in rats fed the control diet alone. DMBA exposure, however, induced significant increases in the lacI MFs in the mammary of both OVX and ovary intact (INT) rats and Hprt MFs in spleen lymphocytes (P相似文献   

Fasting during promotion, but not during initiation, enhances the growth of methylnitrosourea-induced mammary tumours

The purpose of this work was to investigate the effect of fasting on the induction and growth of chemically-induced mammary carcinogenesis. Female Sprague-Dawley rats were given methylnitrosourea (MNU) i.p. (50 mg/kg) at 50 days of age; a group of rats were exposed to 4 day fasting followed by 1 day of refeeding before the administration of the carcinogen, while another group was exposed to three cycles of 3 days fasting in 10 days, beginning 1 week after MNU injection. Fasting enhanced the development of mammary tumours only in rats fasted after carcinogen damage, while it did not affect the induction of tumours in rats fasted before MNU, if compared with full-fed controls. The enhanced growth of mammary tumours sustained by fasting during promotion was observed in the cervical-thoracic region. In addition, exposure to fasting made rats susceptible to the development of MNU- induced extra-mammary cancers. Different from the preventive effect of caloric restriction on tumor development, these data demonstrate that fasting affects the promotion phase of carcinogenesis by enhancing the growth of MNU-induced mammary tumours.      

Net energy effects of dietary fat on chemically induced mammary carcinogenesis in F344 rats

The effect of net energy, as distinct from kilocalorie intake or the percent of fat in the diet, on 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6]-induced mammary tumorigenesis in female inbred F344 rats was investigated. Rats were fed a 5% corn oil diet from weaning until DMBA administration, when they were switched to one of three dietary regimens: 5% corn oil diet, low-fat diet fed ad libitum (LF); 30% corn oil diet, high-fat diet fed ad libitum (HF); or 30% corn oil diet fed at a level providing a calculated net energy equivalent to the group on LF [high-fat diet fed at a restricted level (HF-R)]. Calculated relative net energy values of the amounts of diet actually consumed by the groups on HF-R, LF, and HF were, respectively, 0.90, 1.00, and 1.07 (kcal equivalent to 34.1, 42.2, and 40.8, respectively). Weight gain for the groups on LF and HF-R was the same throughout the experiment (24 wk), while rats on HF weighed significantly more at 6 weeks and thereafter. Body composition analyses at 24 weeks established that the groups on HF and HF-R were equivalent in fat: protein ratio, whereas the group on LF had about 35% less body fat and 15% more body protein. Carcass energy was in the following order for rats in these diet groups: HF greater than HF-R greater than LF. At 24 weeks, tumor incidences for the groups on HF, LF, and HF-R were, respectively, 73, 43, and 7%. These data indicated that tumor appearance does not depend on the percent fat in the diet per se but rather on a complex interaction involving energy intake, energy retention, and body size.