7,12-二甲基苯蒽诱发大鼠乳腺癌的激素依赖性及孕、雌激素受体状况

用DMBA诱发雌性S-D大鼠乳腺癌。给50日龄大鼠每只胃饲20mg DMBA(溶于芝麻油中),一个月后第二次喂药;二次喂药组的发病率高于一次喂药组。从病理形态观察,DMBA诱发乳腺癌以乳腺小叶浸润癌和导管浸润癌为主。87%癌组织??匀浆的ER值大于10fmol/mg蛋白。56%的PR大于10fmol/mg蛋白。切除大鼠双侧卵巢观察此乳腺癌对激素的依赖性表明:65%对卵巢切除有反应性,肿瘤明显缩小。同鼠不同肿块间的ER值、病理形态近似。大鼠乳腺癌ER的特异性与人乳癌相似。试验结果表明:此工作及提供的动物实验模型为进一步研究乳腺癌内分泌治疗的机理和发展新的抗雌激素药物打下基础。     

Stimulation of estradiol-17 beta secretion by 7,12-dimethylbenz (a) anthracene during mammary tumor induction in Sprague-Dawley rats

Testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, estrone and estradiol-17 beta serum levels were measured at given times after dimethylbenz (a) anthracene (DMBA) treatment of a sensitive rat strain Sprague-Dawley (S-D) and a resistant strain Wistar (W). Tumors appeared with a 100% incidence around the 14th to 15th estrous cycle after DMBA treatment in in Sprague-Dawley rats. Hormonal determinations were made, during the 5th or 6th estrous cycle after DMBA treatment, in groups of 4-day cycling rats of both strains which were given DMBA or the carrier solution (sesame oil) when they were about 55-days old. In Sprague-Dawley female rats, DMBA treatment significantly stimulated estradiol-17 beta and estrone preovulatory surge on proestrous days. No such stimulation was found for any other steroid at any time of the estrous cycle. On the other hand, the resistant Wistar rats did not show any disturbed preovulatory or basal steroid hormone release after the carcinogen treatment. These results complete and explain previous findings concerning the hypothalamo-pituitary activity after DMBA treatment of S-D rats: an early and persistent alteration in the centers involved in the hormonal cyclicity of the hypothalamo-pituitary-ovarian axis must be a result of the DMBA treatment. This deregulation could probably account for the distant and selective production of tumors in the mammary gland induced by a single gastric administration of DMBA.     

The binding of 7,12-dimethylbenz[a]anthracene to mammary gland macromolecules in the hamster:effects of Enovid feeding or transplacental exposure to diethylstilboestrol

The covalent binding of 7,12-[3H]dimethylbenz[a]anthracene ([3H--DMBA) to mammary gland macromolecules was studied in hamsters fed a contraceptive mixture, Enovid, those exposed transplacentally to diethylstilboestrol (DES), and controls. Compared with rats, hamsters are relatively resistant to DMBA mammary carcinogenesis, but susceptibility is increased by either of the above treatments with Enovid or DES. The amount of DMBA bound to DNA and protein ws 4-5 times greater than to RNA, but only DNA binding was persistent. Fifty-three percent of the DNA-bound DMBA was still present after 8 days. The amount of DMBA bound to hamster mammary DNA and its persistence was similar to that found in rats. Neither Enovid nor DES treatment altered the levels of binding to mammary macromolecules, nor their persistence. These results indicate that the species differences in the susceptibility to DMBA-induced mammary carcinogenesis in hamsters and rats, and modification of the former by hormones, is not due to differences in the activation of carcinogens. The role of hormones such as prolactin in the promotion phase of mammary gland carcinogenesis may explain these differences.     

Eicosanoid synthesis and ornithine decarboxylase activity in mammary tumors of rats fed varying levels and types of N-3 and/or N-6 fatty acids

Virgin female Sprague-Dawley rats (50 days of age) were administered a single intragastric 10 mg dose of 7,12-dimethylbenz(a) anthracene (DMBA). Three weeks later they were placed on diets containing either 20% corn oil (CO), 20% primrose oil (PO), 20% black currant seed oil (BCO), 20% borage oil (BO), 15% menhaden oil plus 5% corn oil (15% MO + 5% CO), 10% menhaden oil plus 10% corn oil (10% MO + 10% CO), 5% menhaden oil plus 15% corn oil (5% MO + 15% CO) or 10% menhaden oil plus 10% borage oil (10% MO + 10% BO). Incidences of mammary tumors at 16 weeks post-DMBA were 80% in rats fed the CO diet, 84% in rats fed PO diet, 67% in rats fed BCO diet, 88% in rats fed BO diet, 60% in rats fed 15% MO + 5% CO diet, 67% in rats fed 10% MO + 10% CO diet, 83% in rats fed 5% MO + 15% CO diet, and 92% in rats fed 10% MO + 10% BO diet. Tumor multiplicity was lowest in PO-fed rats and highest in BO-fed rats. The tumor burden per tumor-bearing rat was lowest in rats fed the 15% MO + 5% CO, and 10% MO + 10% CO, diets and highest in those fed 20% BCO diet. Although body weight at 16 weeks post DMBA was not significantly different among the dietary groups, food intake was significantly greater in rats fed a diet containing 20% BO, or 5% MO + 15% CO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary polyunsaturated fat and 7,12-dimethylbenz(a)-anthracene on rat splenic natural killer cells and prostaglandin E synthesis

Summary Dietary polyunsaturated fat has been shown to stimulate mammary tumorigenesis induced in rats by 7,12-dimethylbenz(a)anthracene (DMBA). Studies were undertaken to investigate the effect of polyunsaturated fat and DMBA on splenic natural killer (NK) activity and prostaglandin E (PGE) synthesis. In a first experiment, splenic NK activity at 33, 55, 75, and 110 days of age was measured in Sprague-Dawley rats fed 0.5% low fat (LF), 5% normal fat (NF), or 20% high fat (HF) corn oil diets from 23 days of age. At 55 days of age, half of the rats from the 75 and 110 day age groups were given 5 mg DMBA. Ten days after the initiation of the diets splenic NK activity against YAC-1 lymphoma was decreased from 50% cytotoxicity in rats fed NF diet to 21% cytotoxicity in rats fed HF diet, but was not affected by LF feeding. No difference in NK activity was observed among the groups at the later time periods. DMBA had no effect on NK activity at 20 or 55 days after its administration. In a second experiment, where DMBA (15 mg/rat) was given to half of the rats at 50 days of age and NF or HF diets were started 3 days later, NK activity was 35% in rats fed NF diet and 21% in rats fed HF diet, 5 days after the diets were started. No difference in NK activity in rats fed either diet was observed at later time periods. DMBA decreased both NK activity and spleen cellularity transiently. In both experiments, PGE synthesis by spleen cells cultured for 18 h was not affected by dietary fat intake, but was slightly increased 3 days after DMBA administration. Results from these experiments suggest that the stimulation of DMBA-induced mammary tumorigenesis by polyunsaturated fat and by DMBA itself may possibly be mediated by a transient decrease in splenic NK cell activity.This work was supported by grants CA-35641, CA-33240, CA-13038 and Core Grant CA-24538 from the National Cancer Institute     

Alteration of DMBA-induced oxidative stress by additive action of a modified indigenous preparation--Kalpaamruthaa

The present study investigated the protective efficacy of the novel preparation named as Kalpaamruthaa (KA, includes Semecarpus anacardium Linn nut milk extract (SA), dried powder of Phyllanthus emblica fruit and honey) on the peroxidative damage and abnormal antioxidant levels in the hepatic mitochondrial fraction of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma rats. Female Sprague-Dawley rats of weight 180+/-10 g were categorized into six groups. Three groups were administered DMBA (25 mg/rat dissolved in olive oil, orally) to induce mammary carcinoma. One of these groups received KA treatment (300 mg/kg b.wt., orally) and other group received SA (200 mg/kg b.wt., orally) for 14 days after 90 days of DMBA induction. Vehicle-treated control and drug control groups were also included. The hepatic mitochondrial fraction of untreated DMBA rats showed 2.96-fold increase in MDA content when compared to control rats and abnormal changes in the activities/levels of mitochondrial enzymic (superoxide dismutase, glutathione peroxidase and glutathione reductase) and non-enzymic (glutathione, vitamin C and vitamin E) antioxidants were observed. DMBA-treated rats also showed decline in the activities of mitochondrial enzymes such as succinate dehydrogenase, alpha-ketoglutarate dehydrogenase, malate dehydrogenase and isocitrate dehydrogenase. In contrast, rats treated with SA and KA showed normal lipid peroxidation antioxidant defenses and mitochondrial enzymes, thereby showing the protection rendered by SA and KA. Although, KA treatment exhibited more profound effect in inhibiting DMBA-induced oxidative stress than sole SA treatment. Results of the study indicate that the anticarcinogenic activity of KA during DMBA-initiated mammary carcinogenesis is mediated through alteration of hepatic antioxidant status as well as modulation of TCA cycle enzymes. On the basis of the observed results, KA can be considered as a readily accessible, promising and novel cancer chemopreventive agent.     

Influence of estrogen and progesterone on the induction of mammary carcinomas by 7,12-dimethylbenz(a)anthracene in ovariectomized rats.

The influence of estrogen on mammary carcinogenesis was studied in female Sprague-Dawley rats ovariectomized at the age of 36 days and given injections of 17 beta-estradiol (group I:0, II:1, III:10, IV:100, V:1000 micrograms/2 days) between the ages of 36 and 250 days and a single oral dose of 20 mg of 7,12-dimethylbenz(a)anthracene (DMBA) at the age of 50 days. No palpable mammary carcinomas were detected up to the age of 135 days. At the age of 135 days, each group was divided into two subgroups (a and b). Rats of the second subgroup (Ib, IIb, IIIb, IVb and Vb) were given additional injections of progesterone (P; 4 mg/2 days) between the ages of 135 and 250 days. At the age of 250 days, the incidence of mammary carcinoma was significantly higher in rats from group IIIb than in groups Ib and IIIa, and that in group IVa was also higher than in group Ia. The incidence in group IVb was significantly lower than in group IVa. The carcinomas in group IIIb were palpable papillo-tubular adenocarcinomas and those in group IVa were secretory micro-adenocarcinomas. These results indicate that the induction of mammary carcinomas by DMBA is totally inhibited by ovariectomy and/or high doses of estrogen, but that mammary carcinomas are initiated by DMBA under hormonal conditions in which suitable levels of estrogen are present. They also suggest that the growth of DMBA-induced mammary carcinomas in the rats from group III were accelerated by additional injections of P and that those in rats from group IV were inhibited by additional P.(ABSTRACT TRUNCATED AT 250 WORDS)     

Occurrence of mammary tumors in rats after exposure to tritium beta rays and 200-kVp X rays

The RBE for tritium was estimated in reference to 200-kVp X rays, using acceleration of breast tumor appearance in the female Sprague-Dawley rat as the end-point. Chronic X-ray doses of 0.3-2.0 Gy were delivered over 10 days. Intraperitoneal injections of tritiated water ranging in concentrations from 45 to 370 MBq/100 g body wt were administered, followed by four additional injections at 2-day intervals and half of the initial concentrations. Seventy-five percent of the total tritium dose was delivered to the mammary gland within the first 10 days and 95% within the first 20 days after the start of the tritium exposure. RBE estimations were based on various criteria including the tumor incidence per Gy at 450 days postirradiation and the time required to induce tumors in 50% of the animals at risk. The results suggest that tritium beta rays are about 1.1-1.3 times more effective than chronic 200-kVp X rays for acceleration of the appearance of rat mammary tumors. However, the uncertainties involved in these calculations are such that the effects of tritium beta rays could not be reliably distinguished from those of chronic 200-kVp X rays. Measured differences in RBE values were slightly larger for the comparison between acute and chronic X rays than for the comparison between chronic tritium beta rays and chronic X rays.     

Modulatory influences of tamoxifen, tocopherol, retinyl acetate, aminoglutethimide, ergocryptine and selenium on DMBA-induced initiation of mammary carcinogenesis in rats

Present study evaluates the chemopreventive actions of tamoxifen (10 mg/kg), retinyl acetate (50 mg/kg), tocopherol (200 mg/kg), aminoglutethimide (1 mg/kg), ergocryptine (5 mg/kg), and sodium selenite (1 mg/kg) when given singly/in combinations on the initiation of mammary carcinogenesis induced by 20 mg of DMBA in virgin female rats. DMBA was given when rats were 50 days old and the modulators were given in diet 10 days before and 10 days after carcinogen treatment and experiments were terminated 6 months later. DMBA alone yielded tumors in 62% rats. When modulators were given singly and in combinations of two, tumor incidences were not altered significantly. The range of tumor incidences was between 30% and 13% when the agents were given in combinations of 3, 4 and 5. Finally when all 6 modulators were given together the tumor incidence dropped down to 8.3%.     

Do cocarcinogenic effects of ELF electromagnetic fields require repeated long‐term interaction with carcinogens? Characteristics of positive studies using the DMBA breast cancer model in rats

The carcinogenic or cocarcinogenic potential of extremely low frequency (ELF; 50 or 60 Hz) magnetic fields (MFs) has been evaluated worldwide in diverse animal model systems. Though most results have been negative, weakly positive or equivocal results have been reported in several cancer models, including the rat DMBA (7,12-dimethylbenz[a]anthracene) model of mammary cancer. Based on the experimental conditions used in studies in which cocarcinogenic effects of ELF MF were found, it was recently proposed that MF exposure may potentiate the effects of known carcinogens only when the animals are exposed to both MF and carcinogen during an extended period of tumor development, i.e., when the carcinogen is given repeatedly during MF exposure. This review summarizes a series of experiments from our group, showing cocarcinogenic MF effects in the DMBA breast cancer model in rats, to test whether the above proposal is confirmed by existing data. Flux densities of 50 or 100 microT significantly increased the growth of mammary tumors, independent of whether DMBA was given in a single administration or repeatedly over a prolonged period. Thus, these data do not substantiate the hypothesis requiring repeated doses of DMBA during MF exposure. Instead, several other aspects of study design and experimental factors are identified that seem to be critical for the detection of cocarcinogenic effects of MF exposure in the rat DMBA mammary cancer model. These include the rat subline used, the dose of DMBA, the duration of MF exposure, the flux density, the background (sham control) tumor incidence, and the location of mammary tumors in the mammary gland complex. These and other experimental aspects may explain why some laboratories did not detect cocarcinogenic MF effects in the DMBA model. We hope that direct comparison of MF bioeffects in different rat sublines and further evaluation of other experimental differences between studies on MF exposure in the DMBA model will eventually determine which genetic and environmental factors are critical for potential carcinogenic or cocarcinogenic effects of ELF MF exposure.     

Review of the pharmacological properties of toremifene

New compounds were synthesized with the aim to develop new anti-estrogenic antitumor drugs. The biological properties of the molecules were screened by (1) estrogen receptor (ER) binding, (2) effect on MCF-7 cells, (3) uterotrophic effect and inhibition of estradiol induced uterotropic effect and (4) antitumor effect in DMBA induced rat mammary cancer. One of the molecules, Fc-1157a = toremifene, exhibited the following characteristics: competitive inhibition of [3H]estradiol binding to ER (IC50 = 0.3 mumol/l), inhibition of MCF-7 cell growth in a concentration-dependent manner and cell-killing effect at higher than 3 mumol/l concentrations. Minimal estrogenic dose of toremifene on rat uterus weight was about 40 times higher than that of tamoxifen. Toremifene had statistically significant effect against DMBA-induced rat mammary cancer. Further screening consisted of antitumor, pharmacokinetic and safety studies. Toremifene inhibited the growth of ER-negative, glucocorticoid sensitive, mouse uterine sarcoma in a dose-dependent manner. Pharmacokinetics and metabolism of toremifene resembled closely those of tamoxifen, but since the chlorine atom of the toremifene molecule was not metabolically cleaved tamoxifen and toremifene did not have chemically similar metabolites. Toremifene was well tolerated in animal toxicity studies. No hyperplastic or neoplastic nodules, which were seen in almost all high-dose (48 mg/kg for 24 weeks) tamoxifen-treated rats, were found in toremifene-treated rats (dose 48 mg/kg). In clinical phase I studies in healthy voluntary postmenopausal women, no side effects were reported, at doses less than or equal to 460 mg, neither after a single dose nor after five daily doses. At the dose of 680 mg two out of five persons experienced vertigo and headache. Toremifene, at the dose of 68 mg daily, had antiestrogenic effect on estradiol-induced human vaginal epithelial cells. Clinical phase II studies have confirmed that toremifene has a promising antitumor effect.     

Effects of a new antiestrogen, keoxifene (LY156758), on growth of carcinogen-induced mammary tumors and on LH and prolactin levels

Keoxifene (LY156758) is a new benzothiophene-derived antiestrogen with an extremely low degree of estrogenicity. Administration of 1-20 mg/kg per day inhibited the growth of 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumors in rats. The degree of inhibition of mammary tumor growth was similar to that observed with tamoxifen treatment.     

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.     

Charles River Sprague Dawley rats lack early age-dependent susceptibility to DMBA-induced mammary carcinogenesis

Developmental stages of mammary glands influence their susceptibility to initiating events related to carcinogenesis. The "window of susceptibility" to mammary carcinogenesis is classically defined as the time in early puberty when the mammary gland morphology is most sensitive to initiation events. Administration of the polyaromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA), in a single oral dose yields maximal mammary tumor formation when administered in this "window". We examined the DMBA treated mammary glands, precursor lesions, and morphology of the uninvolved mammary epithelium for the first 100 days of life for Charles River Sprague Dawley CD(R) IGS. Our goal was to determine the DMBA dose at which 50% of the rats (IC50) developed carcinoma in situ (CIS) within three months of dosing. Here we demonstrate, rather than the classical U-shaped dose curve in which there is maximum sensitivity for DMBA at 50 days, there is an increasing degree of sensitivity with age in the CD(R) IGS rat. Additionally, we report that vehicle-treated animals developed mammary CIS without any known initiator, and 100 day virgin animals demonstrated lactational changes, independent of DMBA exposure or dose. Lastly, we demonstrate this strain of virgin female rats has elevated pituitary prolactin immunoreactivity independent of the level of mammary differentiation. We conclude this strain of Charles River Sprague Dawley rats has prolactin-induced pituitary stimulation, and therefore, the window of susceptibility for mammary tumorigenesis is absent.     

Mechanisms of DHEA-induced AMH increase in the ovarian tissues of PCOS rat

The present study aimed to build a DHEA-induced polycystic ovary syndrome (PCOS) rat model to evaluate the potential mechanism of DHEA-induced AMH rise in these rat ovarian tissues. A total of 36 female 3-week-old rats were allocated into two groups at random. The control group received merely the same amount of sesame oil for 20 days while the experimental group received 0.2 mL of sesame oil Plus DHEA 6 mg/100 g daily. Both groups' vaginal opening times were noted, and vaginal smears were taken. By using RT-qPCR and Western blot, the mRNA and protein expression of AMH, GATA4, SF1, and SOX9 in the ovarian tissues of the two groups was investigated.The rats in the experimental group appeared to have obvious disorders of the estrus cycle, as evidenced by the ratio of estrus being significantly higher than that in the control group (P < 0.05); HE staining revealed that the ovarian volume, follicular vacuoles, and follicular lumen of the rats in the experimental group increased significantly.The ELISA results revealed that T and AMH in the experimental group were higher than those in the control group at day 15 and 20. AMH、GATA4 and SF1 mRNA and protein expression were higher in the experimental group than in the control group on day 15 and 20 (P < 0.05). On day 20, the experimental group outperformed the control group (P < 0.05). In the DHEA-induced PCOS rat model, androgen may have enhanced AMH expression via increasing the expression of genes associated to the AMH promoter binding site (GATA4, SF1, SOX9).     

High susceptibility of transgenic rats carrying the human c-Ha-ras proto-oncogene to chemically-induced mammary carcinogenesis

A rat line carrying three copies of the human c-Ha-ras proto-oncogenes, including its own promoter region, was established and designated as Hras128. Expression of the transgene was detected in all organs by Northern blot analysis. To examine its influence on susceptibility to mammary carcinogenesis, female rats were treated with N-methyl-N-nitrosourea (MNU) or 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age. With MNU, all the transgenic rats rapidly developed multiple mammary carcinomas within as short as 8 weeks (14.1 tumors/rat), in contrast to 0.46 tumors/rat in non-transgenic rats. PCR-RFLP analysis and direct sequencing for the transgene indicated that the large majority of carcinomas (38/44, 86.4%) contained cells with mutations at codon 12 in exon 1. However, comparison of the signal densities of the mutated band to dilution scale bands revealed that the cells with the mutated transgene were not in the majority. By PCR-SSCP analysis for codons 12 and 61 of the rat endogenous c-Ha-ras gene, no mutations were detected. Similarly, with DMBA, almost all (13/14, 92.9%) the transgenic rats developed multiple mammary carcinomas (9.39 tumors/rat) within 16 weeks, and 4 out of 12 (33.3%) non-transgenic rats had only small tumors (0.83 tumors/rat). A lower incidence of mutation of the transgene was found in codon 12 (5/25, 25%) than in MNU-induced tumors, but mutations were detected in codon 61 (7/20, 35%). No mutations were detected in the rat endogenous gene. No mutation was found in the rat endogenous c-Ha-ras gene in non-transgenic rats. As observed in both the MNU- and DMBA-induced tumor cases, the population of cells with the mutated transgene were in the minority. The results thus indicate that rats carrying the transduced human c-Ha-ras proto-oncogene are highly susceptible to MNU- and DMBA-induced mammary carcinogenesis and that this is not primarily due to mutations of the transgene or endogenous c-Ha-ras gene. Furthermore, irrespective of the mechanism of enhanced susceptibility, the Hras128 transgenic rats can be utilized for the screening of mammary carcinogens.     

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The apperance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.     

Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzanthracene in sprague dawely female rats

Breast cancer is the principle cause of death among women worldwide. In this study, we investigated the anti-tumor potential of lycopene (Lyco) alone or combined with melatonin (Lyco + Mel) for 120 days against a single oral dose of (50 mg/kg B.W.) 7,12-dimethylbenz(a)anthracene (DMBA)-induced oxidative stress and mammary carcinogenesis in female rats. The treatment protocol started from the day immediately after DMBA administration. Results obtained indicated that there was an elevation in the levels of malondialdhyde and nitric oxide in serum and breast tissues of DMBA injected rats. The combined treatment (Lyco + Mel) group showed a potential reduction of these parameters more than lyco individually. The activities of SOD, CAT, and GPx were found to be significantly high than lyco alone treated rats. In DMBA group a negative significant correlation between weight and serum nitric oxide (r = -0.59), and a positive significant correlation between NO and MDA (r = 0.81) was observed. Histopathological examination revealed the formation of tumor and angiogenesis in DMBA-induced rats and these abnormal changes were ameliorated by combined treatment with Lyco + Mel. In conclusion, these results suggested that supplementation of diet with lycopene with melatonin provided antioxidant defense with strong chemo preventive activity against DMBA-induced mammary tumors.     

Restorative Effect of Kalpaamruthaa, an Indigenous Preparation, on Oxidative Damage in Mammary Gland Mitochondrial Fraction in Experimental Mammary Carcinoma

Cancer prevention and treatment using phytochemicals have attracted increased interest. Recent studies have shown that Semecarpus anacardium Linn nut milk extract (SA), a promising antioxidant and anticancer drug, exerts its anticancer effect through reducing or quenching reactive oxygen species under different conditions. The present study examined whether Phyllanthus emblica Linn fruit, rich in vitamin C content synergistically in combination can enhance both the antioxidant and anticancer activity of S. anacardium nut milk extract in 7, 12-dimethyl benz[a]anthracene (DMBA)-induced experimental mammary carcinoma in rat model. Female Sprague Dawley rats of 180 ± 10g were categorized into six groups. Three groups were administered DMBA (25mg/rat, orally) dissolved in olive oil to induce mammary carcinoma. One of these groups received Kalpaamruthaa (KA) (300mg/kg b.wt, orally) and other group received SA (200mg/kg b.wt, orally) for 14 days after 90 days of DMBA induction. A vehicle treated control and drug control groups were also included. The mitochondrial fraction of untreated DMBA-induced mammary gland showed 2.61-fold increase in lipid peroxidation level and abnormal changes in the activities/levels of mitochondrial enzymic (superoxide dismutase, glutathione peroxidase and glutathione reductase) and non-enzymic (glutathione, vitamin C and vitamin E) antioxidants were observed. DMBA treated rats also showed decline in the activities of mitochondrial enzymes such as succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase and isocitrate dehydrogenase. In contrast, rats treated with Kalpaamruthaa showed normal lipid peroxide level and antioxidant defenses. The results of the present study highlight the improved antioxidant property of KA than sole treatment of S. anacardium nut milk extract.     

Effects of magnetic fields on mammary tumor development induced by 7, 12-dimethylbenz(a)anthracene in rats

A series of epidemiological studies have indicated associations between exposure to magnetic fields (MFs) and a variety of cancers, including breast cancer. In order to test the possibility that MF acts as a cancer promoter or copromoter, four separate experiments have been conducted in rats in which the effects of chronic exposure to MFs on the development of mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) were determined. Female rats were exposed in magnetic coils for 91 days (24 h/day) to either alternating current (AC; 50 Hz)-MF or direct current (DC)-MF. Magnetic flux density of the DC-MF was 15 mT. Two AC-MF exposures used a homogeneous field with a flux density of 30 mT (rms); one used a gradient field with flux density ranging from 0.3–1 μT. DMBA (5 mg) was administered orally at the onset of MF exposure and was repeated thrice at intervals of 1 week. In each experiment, 18–36 animals were exposed in 6 magnetic coils. The same number of rats were used as sham-exposed control. These control animals were treated with DMBA and were placed in dummy coils in the same room as the MF-exposed rats. Furthermore, groups of age-matched rats (reference controls) were treated with DMBA but housed in another room to exclude any MF exposure due to the magnetic stray field from the MF produced by coils. At the end of the exposure or sham-exposure period, tumor number and weight or size of tumors were determined at necropsy. Results were as follows: In sham-exposed animals or reference controls, the tumor incidence varied between 50 and 78% in the 4 experiments. The average number of mammary tumors per tumor-bearing animal varied between 1.6 and 2.9. In none of the experiments did MFs significantly alter tumor incidence, but in one of the experiments with AC-MF exposure at 30 mT, the number of tumors per tumor-bearing animal was significantly increased. Furthermore, exposure to a DC-MF at 15 mT significantly enhanced the tumor weight. Exposure to a gradient AC-MF at 0.3–1 μT exerted no significant effects. These experiments seem to indicate that MFs at high flux densities may act as a promoter or copromoter of breast cancer. However, this interpretation must be considered only a tentative conclusion because of the limitations of this study, particularly the small sample size used for MF exposure and the lack of repetition of data. © 1993 Wiley-Liss. Inc.