Carcinogenesis In Female Sprague-Dawley Rats Research Articles

Protective Effects of Antioxidant Chlorophyllin in Chemically Induced Breast Cancer Model In vivo.

Glutathione-related enzymes belong to the protection mechanism of the cells against harmful oxidative damage and chemicals. Glutathione S-transferase (GST) is frequently over-expressed in various cancer cells and is involved in drug resistance. Chlorophyllin is an antioxidant molecule interfering with the GST P1-1 activity. The purpose of this study is to evaluate the short- and long-term protective effects of chlorophyllin as an antioxidant molecule on DNA damage, antioxidant enzyme activities, trace elements, and minerals in chemically induced breast cancer model in vivo. In our study, N-methyl-N-nitrosourea (MNU) was used for inducing breast carcinogenesis in female Sprague-Dawley rats. A total of 36 rats were divided into groups as short term and long term. Each group was divided into four sub-groups as control group received physiological saline solution (n= 3), Chl group (n= 5) received chlorophyllin, MNU group (n= 5) was administered MNU, and Chl + MNU group (n= 5) was treated with both chlorophyllin and MNU. Results illustrated that chlorophyllin had a significant anti-genotoxic effect in the short term, and glutathione-related enzyme activities were protected by chlorophyllin treatment in MNU-induced breast cancer model. Additionally, MNU administration impaired mineral and trace element levels including Na, Mg, K, Fe, Zn, and Co in the liver, kidney, spleen, heart, and tumor tissues; however, adverse effects of MNU were recovered upon chlorophyllin treatment in the indicated tissues of the rats. In conclusion, chlorophyllin can be used as an antioxidant molecule to ameliorate adverse effects of MNU by enhancing antioxidant enzyme activities and regulating trace element and mineral balance in several organs and tumor tissue in the breast cancer model.

Anticancer effect of metformin against 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine-induced rat mammary carcinogenesis is through AMPK pathway and modulation of oxidative stress markers.

Metformin, the type 2 anti-diabetes medication, showed antitumor activity both in vivo and in vitro. This study was carried out to investigate the mechanisms behind the metformin anticancer effect against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female Sprague-Dawley rats. Rats received 10 doses of PhIP (75 mg/kg, p.o., days 1-5 and 8-12). Then, rats were treated with metformin for 26 weeks at a dose of 2 mg/ml in drinking water. Metformin antitumor effect was mediated by increasing the adenosine monophosphate protein kinase (AMPK) activity, liver kinase B1, and decreasing the aromatase and insulin levels compared with the PhIP-administered group. Also, this treatment resulted in a significant decrease in mammary tissue oxidative stress markers and serum lipid profile. In parallel, mammary gland tumors found in PhIP+metformin group were all histologically benign included only (hyperplasia). However, most of the mammary gland tumors found in PhIP group were histologically malignant. These results showed that metformin antitumor effect was mediated through AMPK pathway, reducing oxidative stress and serum lipid levels. This study supports the potential benefit of using metformin as adjuvant therapy during breast cancer treatment.

Effect of allyl isothiocyanate on NF-κB signaling in 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea-induced mammary carcinogenesis.

Inflammation plays a pivotal role in the process of carcinogenesis and phytochemicals have anti-inflammatory properties gaining more importance in cancer chemoprevention. The present study aimed to investigate the anti-inflammatory effect of allyl isothiocyanate (AITC) on 7,12-dimethylbenz(a)anthracene (DMBA)- and N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats. RT-PCR and western blot analysis showed that inflammatory markers such as NF-κB p65, TNF-α, and IL-6 were overexpressed in mammary tumor tissues. Histological analysis of tumor tissues shows abnormality in hematoxylin and eosin (H&E) staining and toluidine blue (TB) staining of mast cell content, and lipid accumulation in oil red O staining. Administration of AITC (20mg/kg bw) to carcinogen-injected rats significantly decreased the expression of NF-κB p65, TNF-α, and IL-6 in mammary tissues. Further, molecular docking study demonstrates the binding of AITC to NF-κB p65. Remarkably, AITC treatments control the growth of cancer cells as clearly evidenced by histopathological analysis. Staining of mammary tissues for mast cells and lipids indicates that AITC treatment to carcinogen-administrated rats significantly reduced mammary tumorigenesis. The result suggests that AITC has anti-inflammatory potential to prevent DMBA- and MNU-induced mammary carcinogenesis in rats.

Polychlorinated Biphenyls Induce Oxidative DNA Adducts in Female Sprague-Dawley Rats.

Polychlorinated biphenyls (PCBs) are organic chemicals that were traditionally produced and widely used in industry as mixtures and are presently formed as byproducts of pigment and dye manufacturing. They are known to persist and bioaccumulate in the environment. Some have been shown to induce liver cancer in rodents. Although the mechanism of the toxicity of PCBs is unknown, it has been shown that they increase oxidative stress, including lipid peroxidation. We hypothesized that oxidative stress-induced DNA damage could be a contributor for PCB carcinogenesis and analyzed several DNA adducts in female Sprague-Dawley rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), and a binary mixture (PCB 126 + 153) for 14, 31, and 53 wks. Eight adducts were measured to profile oxidative DNA lesions, including 8-oxo-deoxyguanosine (8-oxo-dG), 1,N(6)-ethenodeoxyadenosine (1,N(6)-εdA), N(2),3-ethenoguanine (N(2),3-εG), 1,N(2)-ethenodeoxyguanosine (1,N(2)-εdG), as well as malondialdehyde (M1dG), acrolein (AcrdG), crotonaldehyde (CrdG), and 4-hydroxynonenal-derived dG adducts (HNEdG) by LC-MS/MS analysis. Statistically significant increases were observed for 8-oxo-dG and 1,N(6)-εdA concentrations in hepatic DNA of female rats exposed to the binary mixture (1000 ng/kg/day + 1000 μg/kg/day) but not in rats exposed to PCB 126 (1000 ng/kg/day) or PCB 153 (1000 μg/kg/day) for 14 and 31 wks. However, exposure to PCB 126 (1000 ng/kg/day) for 53 wks significantly increased 8-oxo-dG, 1,N(6)-εdA, AcrdG, and M1dG. Exposure to PCB 153 (1000 μg/kg/day) for 53 wks increased 8-oxo-dG, and 1,N(6)-εdA. Exposure to the binary mixture for 53 wks increased 8-oxo-dG, 1,N(6)-εdA, AcrdG, 1,N(2)-εdG, and N(2),3-εG significantly above control groups. Increased hepatic oxidative DNA adducts following exposure to PCB 126, PCB 153, or the binary mixture shows that an increase in DNA damage may play an important role in hepatic toxicity and carcinogenesis in female Sprague-Dawley rats.

Efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. on 7,12-dimethylbenz(a)anthracene induced mammary carcinogenesis in female Sprague-Dawley rats

Neoplastic growth of the breast is the most common malignancy in women worldwide and its incidence has increased in most countries. In this study, we have evaluated the efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. (P. ostreatus) an edible mushroom on modulating levels of xenobiotic metabolizing enzymes, hormonal status of estrogen and progesterone receptor (ER/PR), protein expressions and histopathological analysis in 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis using a rat model. DMBA was induced by single subcutaneous injection at a dosage of 25mg in 1mL vehicle. The ethanolic extract of P. ostreatus (POEet) was administered orally at a concentration of 600mg/kg bwt as pre- and post-initiation stage of treatment throughout the experimental period which was also compared with standard tamoxifen (TAM) (10mg/kg bwt). At the end of 16 weeks, our results showed the elevated phase I and depleted phase II metabolizing enzymes, over expression of (ER/PR) and the expression pattern of the proteins such as fas, fasL, caspase 3, caspase 8, caspase 9, Bax were found to be down regulated whereas p53, Bcl2, cox-2 and cyclin D1 were markedly upregulated in DMBA-induced Sprague-Dawley rats, which were significantly reversed on P. ostreatus administration. Moreover, pre-treatment with P. ostreatus showed improved response when compared to that of posttreatment. Based on scientific appraisal, we conclude that the dietary consumption of P. ostreatus might offer maximum protection against DMBA-induced mammary carcinogenesis and improving human health if used as a regular basis. Focal points•Benchside○ The potential of Pleurotus ostreatus on DMBA induced rat mammary carcinogenesis were determined by the analysis of xenobiotic metabolizing enzymes, hormonal status of ER/PR, as well as the expression of protein using western blotting techniques and histological examination of liver and mammary tissues.•Bedside○ The pharmaceutical potential of P. ostreatus are analysed for is markedly available, edible one with high protein as well as fiber with low fat content and cost effective for patient convenience.•Industry○ Mushrooms are considered as a nutraceutical functional food which can contain enriched prolific produced of novel “mycochemicals” responsible for the human health potential on various diseases and malignancies.•Community○ Standardization and refinement of mycochemical from mushrooms were help to develop the new novel active compounds which contribute for better health and also help to reduce disease burden.•Regulatory agencies○ The P. ostreatus contain several bioactive compounds which might be the key factor for the anticancer effect. This will need to be taken for labeling and pattering the compounds and tested in clinical trials.

Dose response chemopreventive potential of allyl isothiocyanate against 7,12-dimethylbenz(a)anthracene induced mammary carcinogenesis in female Sprague-Dawley rats

The present study aimed to investigate the dose response chemopreventive potential of allyl isothiocyanate (AITC) against 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. Mammary tumor was induced by a single dose of DMBA (25mg/rat) injected subcutaneously near mammary gland. We observed reduced body weight and increased in total number of tumors, tumor incidence and tumor volume in DMBA-induced rats. We also observed decreased antioxidant status (SOD, CAT, GPX and GSH) and increased lipid peroxidation (TBARS and LOOH) in plasma and mammary tissues. Increased levels of CYP450, Cyt-b5 and decreased levels of phase II (GST and GR) biotransformation enzymes noticed in liver and mammary tissues of DMBA-induced rats. Further, increased levels of lipid profile (TC, TG, PL and FFA) and lipoprotein (LDL and VLDL) were noticed. Whereas, decreased level of HDL in plasma and decreased levels of PL and FFA in mammary tissue. Oral administration of AITC different doses (10, 20 and 40mg/kgbw) inhibited the tumor incidence and restored levels of biochemical markers. Biochemical findings are supported by histopathological studies. These results suggested that AITC at a dose of 20mg/kgbw significantly exert chemopreventive potential against DMBA-induced mammary carcinogenesis.

Combination of Pitavastatin and melatonin shows partial antineoplastic effects in a rat breast carcinoma model

Our previous results indicated significant tumor-suppressive effects of different statins in rat mammary carcinogenesis. The purpose of this experiment was to examine the chemopreventive effects of Pitavastatin alone and in combination with the pineal hormone melatonin in the model of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats. Pitavastatin was administered dietary (10mg/kg) and melatonin in an aqueous solution (20μg/ml). Chemoprevention began 7 days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumors were removed and prepared for histopathological and immunohistochemical analysis. Compared to controls, Pitavastatin alone reduced average tumor volume by 58% and lengthened latency by 8 days; on the other hand, the drug increased tumor frequency by 23%. Combined administration of Pitavastatin with melatonin decreased tumor frequency by 23%, tumor volume by 44% and lengthened tumor latency by 5.5 days compared to control animals. The analysis of carcinoma cells showed significant increase in caspase-3 expression in both treated groups and a tendency of increased caspase-7 expression after Pitavastatin treatment alone. Significant expression decrease of Ki67 was found in carcinoma cells from both treated groups. Compared to control carcinoma cells, Pitavastatin alone increased VEGF expression by 41%, however melatonin totally reversed its undesirable effect. Pitavastatin combined with melatonin significantly increased femur compact bone thickness in animals. Pitavastatin alone decreased plasma triglycerides and total cholesterol levels, however it significantly increased levels of glucose. In summary, our results show a partial antineoplastic effect of Pitavastatin combined with melatonin in the rat mammary gland carcinoma model.

Chemopreventive effect of montelukast in n-nitroso n-methyl urea induced mammary carcinogenesis in female Sprague-Dawley rats

Objective:The objective of the study was to evaluate the chemopreventive effect of montelukast sodium; selective reversible cysteinyl leukotriene D4-receptor antagonist in N-nitroso N-methyl urea (NMU) induced mammary carcinogenesis in virgin female Sprague-Dawley rats.Materials and Methods:Thirty rats were divided into five groups (normal control, disease control, montelukast1 mg/kg, montelukast10 mg/kg, tamoxifen10 mg/kg) of six animals each. The drug was administered in two doses,1 mg/kg,and 10 mg/kg orally and compared with the standard drug tamoxifen (10 mg/kg)p.o.Results:Montelukast sodium 1 mg/kg,10 mg/kg, and tamoxifen10 mg/kg decreased the tumor incidences by 50%,66.67%, and 83.33% and the total number of tumors in group by 41.67%, 58.33% and 91.67% respectively, when compared to the disease control. Montelukast sodium 1 mg/kg,10 mg/kg,and tamoxifen10 mg/kg decreased the average tumor burden by 86.41%,94.8% and 95.97%and average tumor volume by 89.52%, 95.84%, and 95.4%respectively, when compared to disease control group.Conclusion:The results revealed that montelukast sodium prevent the mammary carcinogenesis and confirms the role of cysteinyl leukotriene D4-receptor in mammary gland neoplasia.

Combined supplementation of vanadium and fish oil suppresses tumor growth, cell proliferation and induces apoptosis in DMBA‐induced rat mammary carcinogenesis

The anti-cancer activity of vanadium and fish oil has been shown in a large number of studies. This study was undertaken to analyze the combined effect of vanadium and fish oil on 7,12-dimethylbenz(α)anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. The whole experiment was divided into three parts: (1) DNA strand breaks study, (2) morphological analysis, and (3) histological and immunohistochemical study. Rats were treated with DMBA (0.5 mg/0.2 ml corn oil/100 g body weight) by a tail vein injection. Rats received vanadium (w/v) as ammonium monovanadate at a concentration of 0.5 ppm (4.27 µmol/L) in the drinking water and given ad libitum and/or fish oil (0.5 ml/day/rat) by oral gavage. Histology, morphology, DNA strand breaks, cell proliferation, and apoptosis of the mammary tissue were assessed in this study. Treatment with vanadium or fish oil alone significantly reduced the DNA strand breaks, palpable mammary tumors, tumor multiplicity, and cell proliferation but the maximum protection effect was found in the group that received both vanadium and fish oil and the combination treatment offered an additive effect (P < 0.05). Furthermore, vanadium and fish oil significantly increased the TUNEL-positive apoptotic cells (P < 0.05) but the increase was maximal with combination treatment and had an additive effect. These results affirm the benefits of administration of vanadium and fish oil in the prevention of rat mammary carcinogenesis which was associated with reduced DNA strand breaks, palpable mammary tumors and cell proliferation and increased TUNEL-positive apoptotic cells.

Assessment of female reproductive endpoints in Sprague–Dawley rats developmentally exposed to Diuron: potential ovary toxicity

Diuron is widely used in agriculture but its deleterious effects on the reproductive system and mammary gland are still poorly understood. This study evaluated whether early-life-stage exposure to Diuron alters puberty onset or susceptibility to mammary carcinogenesis in female Sprague-Dawley rats. Pregnant rats received basal diet or diet containing Diuron at 500, 750, and 1,250 ppm, from gestational day 12 to the end of lactation (postnatal day 21 [PND21]). After weaning, female offspring continued receiving basal diet or diet containing Diuron until PND 51. At PND 51, female Sprague-Dawley offspring received a single dose of 50 mg/kg b.w. of 7,12-dimethylbenz(a)anthracene (DMBA) for initiation of mammary carcinogenesis. The animals were sacrificed on PND 51, 75, and 226 to 233 (week 25) for mammary gland morphology, reproductive organs and tumor analysis, respectively. There were no significant differences among groups on vaginal opening, estrous cycle, mammary morphology, or carcinogenesis. However, reductions in ovary weight and corpora lutea were observed at PND 75 in the group treated with Diuron at 1,250 ppm. The findings suggesting that Diuron exposure (1,250 ppm) may have been potentially toxic to the ovaries.

Genistein and daidzein, in combination, protect cellular integrity during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in Sprague-Dawley rats.

The status of glycoconjugates (protein bound hexose, hexosamine, sialic acid and fucose) in plasma or serum serve as potential biomarkers for assessing tumor progression and therapeutic interventions. Aim of the present study was to investigate the protective effect of two major soy isoflavones, genistein and daidzein, in combination on the status of glycoconjugates in plasma, erythrocyte membrane and mammary tissues during 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. A single subcutaneous injection of DMBA (25 mg rat(-1)) in the mammary gland developed mammary carcinoma in female Sprague-Dawley rats. Elevated levels of plasma and mammary tissue glycoconjugates accompanied by reduction in erythrocyte membrane glycoconjugates were observed in rats bearing mammary tumors. Oral administration of genistein + daidzein (20 mg + 20 mg kg(-1) bw/day) to DMBA treated rats significantly (p< 0.05) brought back the status of glycoconjugates to near normal range. The present study thus demonstrated that genistein and daidzein in combination protected the structural integrity of the cell surface and membranes during DMBA-induced mammary carcinogenesis.

Influence of diet enriched with conjugated linoleic acids on their distribution in tissues of rats with DMBA induced tumors

BackroundConjugated linoleic acids (CLA) are a group of positional and geometric isomers of linoleic acid with proven beneficial influence on health. They show e.g. anticarcinogenic, antiobesity, and antiatherogenic effect. Milk, dairy products and meat of poligastric animals are their most valuable dietary sources, with cis-9, trans-11 CLA (RA - rumenic acid) being the predominant isomer. Dietary supplements with CLA became very popular, mainly among the overweight and bodybuilders.The aim of this study was to examine the influence of the food supplements with conjugated linoleic acid on carcinogenesis in female Sprague-Dawley rats and evaluation of CLA and other fatty acids distribution in their bodies.Animals were divided into four groups depending on the diet supplementation (oil or Bio-C.L.A. (Pharma Nord Denmark) given intragastrically) and presence or absence of carcinogenic agent (7,12-dimethylbenz[a]antharcene). Animals were decapitated at 21st week of experiment and serum and microsomes were extracted.Results and conclusionsThe mammary tumours (adenocarcinoma) occurred in groups treated with DMBA. Diet enriched with CLA decreased the cancer morbidity (67% in Bio-C.L.A. compared to 88% in oil) and delayed the cancer induction (p = 0.0018). There were no differences in body and organs weight.The supplement used in the study was a mixture of several fatty acids with the greatest proportion of CLA isomers: trans-10, cis-12 (33%) and cis-9, trans-11 (31%). Both of them were present in tissues but the content of rumenic acid was greater. Dietary supplementation had also significant impact on other fatty acids content, both in serum and in microsomes.

Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats

BackgroundBreast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer.MethodsThe effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU) induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot.ResultsAuraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to the MNU only group (p < 0.05, n = 24–26). Auraptene (10 μM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells. In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group. Analysis of rat mammary tissue extract by HPLC with fluorescence detection indicated an average concentration (means ± S.E.) of 1.4 ± 0.5 μM and 1.8 ± 0.3 μM in the normal mammary glands of the auraptene 200 ppm and 500 ppm groups, respectively. The concentration (means ± S.E.) of auraptene in the mammary tumors of the auraptene 200 ppm group was 0.31 ± 0.98 μM.ConclusionOverall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene in mammary carcinogenesis.

Side effects of anastrozole in the experimental pre-menopausal mammary carcinogenesis

The aim of this study was to assess side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats. This model mimicked situation in healthy, but from the point of view of the development of breast cancer, high-risk pre-menopausal women. <p align="justify">Aromatase inhibitor anastrozole was used as a chemopreventive agent taken by the animals in the food during the whole period of time of the experiment. Group 1 - the control group had taken food without anastrozole, the groups 2 and 3 with anastrozole in various concentrations - 0.05 mg/1 kg of food (ANA 0.05) and 0.5 mg/1 kg of food (ANA 0.5). </p><p align="justify">In anastrozole-treated animals in comparison with untreated animals, macroscopic changes of uterus and vagina were not found. The values of absolute and relative wet weight of uterus and vagina in the groups ANA 0.05 and ANA 0.5 were comparable with the control. Histological examination did not show atrophic changes in endometrium of uterus and in epithelium of vagina in anastrozole-treated animals. In the group ANA 0.5 myometrium was significantly grosser than in the group ANA 0.05 (P<0.05). Anastrozole neither affects parameters of plasma lipid metabolism (triacylglycerols, total cholesterol, low - density lipoprotein cholesterol and high - density lipoprotein cholesterol) nor serum levels of sex hormones (estradiol, testosterone, dehydroepiandrosterone). Compact bone thickness in the groups with anastrozole was significantly increased in comparison with untreated animals (P<0.001). A significant increase in body weight was found in the group ANA 0.5 compared with the control group (P<0.01). The significant increase in body weight gain was not attended by the significant increase in food intake.</p><p align="justify">The side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats on myometrium, compact bone thickness and body weight gain were observed. </p> pre-menopausal mammary carcinogenesis, chemoprevention, aromatase inhibitors, anastrozole, side effects, female rats.

Metformin in chemically-induced mammary carcinogenesis in rats

In this paper the chemopreventive effect of peroral antidiabetic metformin in mammary carcinogenesis in female Sprague-Dawley rats was evaluated. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea (NMU) administered in two intraperitoneal doses each per 50 mg/kg b.w. between 43.-55. postnatal days. Metformin was administered in drinking water (at a concentration of 50 microg/ml and 500 microg/ml) 13 days before the first NMU dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors, the incidence, latency, tumor frequency, and tumor volume were recorded. The experiment was terminated 18 weeks after the first NMU dose, basic tumor growth parameters and metabolic and hormonal variables were evaluated. Metformin did not significantly alter the tumor growth although a delay in tumor onset was recorded after higher metformin dose. Metformin altered metabolic and hormonal variables. Insulinemia decreased after both metformin doses in comparison with intact rats without changes in glycemia, triacylglycerols concentration was decreased in liver and increased in serum when compared to intacts. Higher metformin dose attenuated lipoperoxidation in liver.

Effect of a Short-Term and Long-Term Melatonin Administration on Mammary Carcinogenesis in Female Sprague-Dawley Rats Influenced by Repeated Psychoemotional Stress

The aim of this study was to evaluate the effect of melatonin (MEL) on N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in female Sprague-Dawley rats exposed to repeated psychoemotional stress - immobilization in boxes. NMU was applied intraperitoneally in two doses each of 50 mg/kg b.w. between 40 - 50 postnatal days. Melatonin was administered in drinking water at a concentration of 4 μg/ml daily from 15:00 h to 8:00 h. The application was initiated 5 days prior to the fi rst NMU dose and lasted 15 days, i.e. during the promotion phase of tumour development, or long-term until the end of the experiment (week 20). Immobilization (2 h per day) began on the third day after the second carcinogen application and lasted for 7 consecutive days. Short-term MEL administration to immobilized animals increased incidence by 22%, decreased tumour frequency per animal by 26% and reduced tumour volume gain (by 21%) when compared to the immobilized group without MEL application. Decreased frequency per animal by 28% and more than a 40% decrease in tumour volume gain and cumulative volume were the most pronounced changes in the animals drinking MEL until the end of the experiment. Long-term MEL administration reduced the number and size of mammary tumours more markedly than its short-term administration. Melatonin decreased certain attributes of mammary carcinogenesis in female rats influenced by psychoemotional stress.

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.

Retinyl Acetate and Melatonin in Chemoprevention of Mammary Carcinogenesis in Female Rats: Metabolic Changes

home Acta Veterinaria Brno Journal of the University of Veterinary Sciences Brno, Czech Republic Search:

Antimutagenic and anticarcinogenic potentials of some Thai vegetables

Fifteen kinds of commonly consumed Thai vegetables were sequentially extracted with hexane, chloroform and methanol, and then tested for antimutagenic activities against direct-acting (AF-2 and NaN 3) and indirect-acting (AFB 1 and B( a)P) mutagens using Ames' Salmonella mutagenicity test with Salmonella typhimurium TA100 as tester strain. It was found that only the methanol extract of neem leaves contain weak antimutagen inhibiting the mutagenicities of both direct-acting mutagens. Interestinglly, all vegetables studied were found to contain chemical compounds, mainly nonpolar ones, capable of inhibiting the mutagenicity of AFB 1, while only some vegetables contain chemical compounds capable of inhibiting the mutagenicity of B( a)P, which is also an indirect-acting mutagen. Studies on anticarcinogenic potentials demonstrated that Thai bitter gourd fruits, but not sweet basil leaves, at the concentration of 6.25% and 12.5% in the diet, partially inhibited DMBA-induced mammary gland carcinogenesis in female Sprague-Dawley rats when fed to the animals 2 weeks prior to DMBA. Results in the present study therefore demonstrated that most Thai vegetables contain antimutagens inhibiting the mutagenicity of some indirect-acting mutagen, particularly AFB 1. The mechanism of their antimutagenicity may probably be the inhibition of the activity of metabolic-activating enzymes in rat liver homogenates. Very interestingly, our results clearly reveal that Thai bitter gourd fruits, which possess Phase II enzymes inducing property, as well as the ability to reduce Phase I enzyme activities in rat liver, contain some anticarcinogens or chemopreventive agents. However, sweet basil leaves that possess both Phase I and Phase II enzyme-inducing properties may not contain any anticarcinogen, at least against DMBA-induced mammary gland carcinogenesis.

Effects of type and level of dietary fat during the pre-initiation phase of mammary carcinogenesis in rats

The effects of feeding two types (corn and menhaden) and two levels (5% and 20%, w/w) of dietary fat administered during the pre-initiation phase of chemically-induced mammary carcinogenesis on serum fatty acid profiles, and on tumorigenesis were studied in female Sprague-Dawley rats. One hundred and twenty 4-wk old rats were randomly divided into 4 groups and given the experimental diets for 4 weeks. When the rats were 8 weeks old, a single dose (5 mg/100 g body wt) of 7,12 dimethylbenz(α) anthracene (DMBA) was administered intragastrically to each rat. Thereafter, all the rats were fed the AIN-76A diet until the termination of the experiment. All the rats were necropsied 14 weeks after carcinogen administration. Body weights among the four groups of rats were similar throughout the study and was not different at necropsy. At the end of the experiment (14 weeks post-DMBA), the palpable tumor incidence was not significantly different (P > 0.05) among the four groups of rats, but at 12 weeks post-DMBA, the 20% corn oil (HCO) and the 5% menhaden oil (LMO) groups had significantly higher tumor incidence than the 20% menhaden oil (HMO) and the 5% corn oil (LCO) groups. Tumor burden (total tumor weight/rat) and mean latent period were not significantly different. Serum fatty acid profiles reflected the type of dietary oils consumed by the rats. These results showed that neither the type (corn, menhaden) nor the amount (5%, 20%) of dietary fat fed during pre-initiation influenced the final outcome of mammary carcinogenesis in female Sprague-Dawley rats.