RESUMO
We compared the effects of chronic treatment with 2-Br-alpha-ergocryptine (CB-154) and of ovariectomy on the genesis of mammary hyperplastic nodules (HN) and mammary tumors in the C3H/He mouse. CB-154 is an established potent suppressor of pituitary prolactin. Eighty-five 21- to 25-day-old female mice were divided into three groups. Group I received daily sc injections of 0.1 mg CB-154. Group II was ovariectomized and group III served as controls. Mice were examined weekly for mammary tumors. Fifteen months from onset of treatment all surviving mice were killed. The mean number of HN per inguinal mammary gland, total number of mammary tumors, and number (percent) of mice with mammary tumors in each group were, respectively: controls--4.6 +/- 1.1, 41, 24/29 (83%); ovariectomized--1.2 +/- 0.6, 20, 14/28 (50%); and CB-154-treated--0.2 +/- 0.1, 16, 13/28 (46%). A significant (P less than 0.001) and equally comparable inhibition of mammary tumor incidence was observed in the ovariectomized and CB-154-treated mice. Thus early ovariectomy and CB-154 treatment (specific inhibition of prolactin secretion) appeared equally effective in the prophylaxis of mammary tumorigenesis in the C3H/He female mouse.
Assuntos
Bromocriptina/uso terapêutico , Castração , Ergolinas/uso terapêutico , Neoplasias Mamárias Experimentais/terapia , Lesões Pré-Cancerosas/terapia , Glândulas Suprarrenais/patologia , Animais , Feminino , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Lesões Pré-Cancerosas/metabolismo , Prolactina/metabolismoRESUMO
The effect of high levels of dietary fat and retinyl acetate (ROA) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor development and growth was examined. Female Sprague-Dawley rats, 51-53 days of age, were treated ig with 5 mg DMBA. At 55-57 days of age, the animals were divided into the following dietary treatment groups: A) 4.5% fat [control fat (CF)]; B) CF + 1.0 mmol ROA/kg diet (CF + ROA); C) 20.0% fat [high fat (HF)]; and D) HF + ROA. HF diets significantly increased mammary tumor multiplicity, with or without ROA, but did not significantly influence mammary tumor growth. ROA treatment reduced mammary tumor multiplicity regardless of the level of dietary fat and inhibited mammary tumor growth in the presence of normal levels of dietary fat. High levels of dietary fat did not significantly influence normal mammary gland growth and development. ROA significantly decreased normal mammary gland growth and development regardless of the level of dietary fat. Blood retinoids in rats fed ROA were primarily in the form of retinyl esters, i.e., retinyl linoleate, retinyl palmitate-oleate, and retinyl stearate. Free retinol levels in blood were not significantly influenced by ROA feeding. Blood retinyl ester levels were lower in rats fed the HF + ROA diet as compared to rats fed the CF + ROA diet.
Assuntos
9,10-Dimetil-1,2-benzantraceno , Gorduras na Dieta/administração & dosagem , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Experimentais/induzido quimicamente , Vitamina A/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Cocarcinogênese , Gorduras na Dieta/farmacologia , Diterpenos , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos Endogâmicos , Retinoides/sangue , Ésteres de Retinil , Fatores de Tempo , Vitamina A/sangue , Vitamina A/farmacologiaRESUMO
Feeding of retinyl acetate (82 mg/kg ration) for 13-16 weeks to estrone- and progesterone-treated nulliparous and multiparous inbred GR/A mice resulted in a substantial increase in the incidence of mammary carcinomas. Mammary carcinoma incidence in nulliparous control and retinoid-fed mice in experiment #1 was 22/65 (34%) and 37/65 (57%) (P less than 0.05), respectively; in experiment #2, 27/48 (56%) and 37/48 (77%) (P less than 0.05), respectively. Mammary carcinoma incidence in multiparous control and retinoid-fed mice in experiment #1 was 13/30 (43%) and 23/30 (77%) (P less than 0.05), respectively; in experiment #2, 19/19 (100%) and 19/19 (100%), respectively. The purported chemopreventive activities of retinyl acetate in murine mammary tumorigenesis were not demonstrated in this study; indeed, the vitamin A analog appeared to enhance this oncogenic process in the steroid hormone-treated GR mouse mammary cancer model.
Assuntos
Estrona , Neoplasias Mamárias Experimentais/induzido quimicamente , Progesterona , Vitamina A/análogos & derivados , Animais , Cocarcinogênese , Diterpenos , Feminino , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Paridade , Ésteres de Retinil , Vitamina A/farmacologiaRESUMO
Vaginal adenosis biopsy specimens from 10 patients exposed in utero to diethylstilbestrol were transplanted for 30 days into athymic (nude) mice. Almost all grafts were recovered, and they had morphologic features closely resembling those of the original biopsy specimens, i.e., cystic, complex, and simple occult glands covered mainly with an endocervical type of epithelium showing extensive squamous metaplasia. Autoradiographic analysis of these grafts after pulse administration of [3H]thymidine into the mice revealed extensive labeling of epithelial cells. These results imply that female athymic (nude) mice are compatible hosts for accretion of the human adenosis.
Assuntos
Dietilestilbestrol/efeitos adversos , Doenças Vaginais/patologia , Adolescente , Adulto , Animais , Dietilestilbestrol/administração & dosagem , Feminino , Humanos , Troca Materno-Fetal , Camundongos , Camundongos Nus , Gravidez , Transplante Heterólogo , Doenças Vaginais/induzido quimicamenteRESUMO
Female 55-day-old Sprague-Dawley rats were treated with a single intravenous dose of 7,12-dimethylbenzanthracene (DMBA), 2 mg/100 g of body weight each. At 60 days of age, the rats were divided into four dietary groups (41-42 rats/group):I, 5% corn oil diet fed ad libitum; II, 20% corn oil diet fed ad libitum; III, 5% corn oil diet fed 12% less than group I; and IV, 20% corn oil diet fed 12% less than group II. The 5% and 20% corn oil diets were purified semisynthetic diets that were isonutrient on a caloric basis. All animals were housed individually in single cages; food consumption of each animal was computed daily throughout the study. Sixteen weeks after carcinogen treatment, mean numbers of mammary carcinomas per rat (+/- SE) in groups I, II, III, and IV were 4.1 +/- 0.6, 6.8 +/- 0.7, 3.0 +/- 0.3, and 4.1 +/- 0.5, respectively. Mean weight of mammary carcinomas per rat (g +/- SE) in groups I, II, III, and IV were 3.5 +/- 0.7, 8.0 +/- 1.3, 3.0 +/- 1.1, and 4.6 +/- 1.3, respectively. Mammary carcinoma number and weight were significantly (P less than .01) increased in the animals fed the 20% corn oil diet ad libitum when compared with those fed the 5% corn oil diet ad libitum; however, no significant differences in mammary tumor number or weight were observed between the animals fed a restricted, 20% corn oil diet and those fed a restricted, 5% corn oil diet. The study involving the animals fed the 12%-restricted diets was repeated (38-42 rats/group), with virtually identical results, i.e., the mean number of mammary carcinomas per rat in the groups fed the restricted 5% fat and 20% fat diets at termination of the study was 3.1 +/- 0.4 and 3.7 +/- 0.3, respectively, and the mean weight (g) of mammary carcinomas per rat was 4.3 +/- 1.2 and 4.0 +/- 1.1, respectively (no significant differences). Thus, high levels of dietary fat can significantly enhance mammary carcinogenesis in female rats, but only in animals on an ad libitum feeding protocol. A slight restriction in amount consumed (12% less than ad libitum) abolished the mammary carcinogenic differential between a high-fat and a low-fat diet.
Assuntos
Gorduras na Dieta/administração & dosagem , Ingestão de Alimentos , Neoplasias Mamárias Experimentais/etiologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Ingestão de Energia , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/epidemiologia , Ratos , Ratos Endogâmicos , Aumento de PesoRESUMO
Transplantation success rates of primary 7,12-dimethylbenz(a)anthracene [(DMBA) CAS: 57-97-6]-induced rat mammary carcinomas and normal rat mammary glandular epithelium into female athymic mice were compared. The rat mammary carcinomas obtained from female Sprague-Dawley rats were transplanted into host athymic mice (6-8 wk of age) as 1 x 1-cm slices xenografted sc (2 slices/mouse) or as enzymatically dissociated cells inoculated into the gland-free mammary fat pad. Normal rat mammary glands (No. 4 glands and 3- to 5-mo-old virgin rats) were transplanted into host athymic mice as whole, intact mammary glands sc (1 gland/mouse) or as enzymatically dissociated cells inoculated into the gland-free mammary fat pad. All (100%) of the normal rat mammary glands were readily accepted and maintained in the athymic mice when transplanted either sc as whole glands or as dispersed cells inoculated into the gland-free fat pad. In contrast, only 13-14% of the DMBA-induced rat mammary carcinomas were accepted and maintained in the athymic mice (transplanted as slices sc or as dispersed cells inoculated into the gland-free fat pad). Treatment of host athymic nude mice with an intense mammotropic hormonal stimulus (prolactin and/or ovarian steroids) markedly enhanced the developmental growth of the transplanted normal rat mammae (subcutaneous slices and fat-pad inoculates); such a hormonal stimulus did not influence the transplantation success rate of the DMBA-induced rat mammary carcinomas. Thus female athymic nude mice can readily accept and maintain transplants of normal rat mammae but not carcinogen-induced carcinomatous rat mammae; the meager acceptance rate of the carcinomatous rat mammae by the athymic nude mouse was not enhanced by providing the host mice with a potent mammotropic hormonal growth stimulant.
Assuntos
Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/patologia , Transplante de Neoplasias , 9,10-Dimetil-1,2-benzantraceno , Animais , Epitélio/patologia , Estrogênios/farmacologia , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Glândulas Mamárias Animais/transplante , Neoplasias Mamárias Experimentais/induzido quimicamente , Camundongos , Camundongos Nus , Perfenazina/farmacologia , Neoplasias Hipofisárias/patologia , Ratos , Ratos Endogâmicos , Transplante HeterólogoRESUMO
The effect of high levels of dietary fat on the promotion phase of rat mammary tumorigenesis and the effect of unsaturated and saturated fatty acids on metabolic cooperation in hamster cells were examined. Female Sprague-Dawley rats were given iv injections of 5 mg 7,12-dimethylbenz[a]anthracene (DMBA) and subsequently placed on 20% high-fat (HF) and 4.5% corn oil control (CF) diets. Rats treated with DMBA and fed HF diet for the entire duration of the experiment developed more tumors with shorter latency than rats fed CF diet for the entire experiment. Rats fed HF diet for 3 weeks at different times after DMBA treatment showed similar, enhanced mammary tumor development. Lengthening the duration of HF diet treatment (0, 3, 6, 16 wk) increased mammary tumor development, suggesting a time dose-response relationship. Removal of the HF diet treatment partially reversed its stimulatory effects on tumor development. These results indicate that dietary fat acts as a classical tumor promoter to enhance mammary tumorigenesis. The influence of unsaturated and saturated fatty acids on metabolic cooperation between 6-thioguanine-sensitive (6-TGS) and 6-thioguanine-resistant (6-TGr) Chinese hamster V79 cells was examined. Linoleic acid, palmitoleic acid, and arachidonic acid significantly increased the recovery of 6-TGr cells at noncytotoxic concentrations. Stearic acid, palmitic acid, and arachadic acid had no effect on the recovery of 6-TGr cells at either cytotoxic or noncytotoxic concentrations. These results demonstrate that unsaturated fatty acids but not saturated fatty acids can inhibit metabolic cooperation between Chinese hamster V79 cells, and suggest, mechanistically, that high dietary levels of polyunsaturated fat could promote tumorigenesis by inhibition of intercellular communication.
Assuntos
Comunicação Celular , Gorduras na Dieta , Neoplasias Mamárias Experimentais/fisiopatologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Cricetinae , Cricetulus , Feminino , Ácido Linoleico , Ácidos Linoleicos/farmacologia , Pulmão , Ratos , Ratos Endogâmicos , Ácidos Esteáricos/farmacologia , Tioguanina/farmacologia , Fatores de TempoRESUMO
One hundred sixty-eight female Lewis rats were treated intragastrically with 10 mg 7,12-dimethylbenz[a]anthracene at 56 and 63 days of age. Pituitary prolactin secretion was suppressed in one-half of these rats by daily sc administrations of 2-bromoergocryptine mesylate (CB-154; 0.4 mg/100 g body wt) from 29 to 90 days of age (series 1) and from 90 to 140 days of age (series 2). Treatment with CB-154 was initiated prior to the onset of palpable mammary carcinomas. Control rats were given injections of saline. Inguinal mammary glands were excised from 10 control and 10 CB-154-treated rats at the cessation of saline and CB-154 treatments and examined for hyperplastic nodules (HN). The remaining rats were palpated weekly for mammary carcinomas (MC) and killed at 200 days of age. Mean number of HN per rat, mean number of MC per rat, and percent of rats with MC were, respectively: series 1--controls, 0.6, 1.5, and 68; CB-154 treatment, 0.5, 1.1, and 62; series 2--controls, 10.4, 2.0, and 94; CB-154 treatment, 5.1, 1.1, and 56. The number of HN and MC was only slightly reduced in rats when prolactin was suppressed during carcinogen treatment (series 1) but markedly reduced when prolactin was suppressed after carcinogen treatment (series 2). These results provide evidence that prolactin is involved in the early development of mammary dysplasias in the carcinogen-treated female Lewis rat.
Assuntos
Neoplasias Mamárias Experimentais/prevenção & controle , Prolactina/metabolismo , 9,10-Dimetil-1,2-benzantraceno , Animais , Bromocriptina/farmacologia , Feminino , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Hormônio-Dependentes/prevenção & controle , Lesões Pré-Cancerosas/prevenção & controle , Prolactina/fisiologia , Ratos , Fatores de TempoRESUMO
The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.
Assuntos
Neoplasias Mamárias Experimentais/induzido quimicamente , 9,10-Dimetil-1,2-benzantraceno , Corticosteroides/fisiologia , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Castração , Cocarcinogênese , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Hormônios Esteroides Gonadais/fisiologia , Insulina/fisiologia , Masculino , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Metilcolantreno , Metilnitrosoureia , Transplante de Neoplasias , Nucleotídeos Cíclicos/farmacologia , Hormônios Adeno-Hipofisários/fisiologia , Prostaglandinas/farmacologia , Ratos , Retinoides/farmacologia , Selênio/farmacologia , Hormônios Tireóideos/fisiologia , Vitamina E/farmacologiaRESUMO
That dietary fat can significantly affect mammary tumorigenesis in mice and rats has been clearly established. The purpose of this communication is to review and critique this interesting and potentially important relationship. This review focuses on the relationship between the amount and type of dietary fat and the role of calories in rodent mammary tumor development and metastasis. Additionally, the influence of dietary fat on development of human breast carcinoma transplants in immunodeficient mice is examined. The numerous studies cited in this review provide a compelling biological foundation for a potentially important relationship between dietary fat and/or calorie consumption and breast carcinoma development in human populations.
Assuntos
Gorduras na Dieta/efeitos adversos , Ingestão de Energia , Neoplasias Mamárias Experimentais/etiologia , Animais , Neoplasias da Mama/patologia , Gorduras na Dieta/administração & dosagem , Ácidos Graxos/administração & dosagem , Ácidos Graxos/efeitos adversos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/efeitos adversos , Feminino , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Metástase Neoplásica , Transplante de Neoplasias , RatosRESUMO
Daily treatment (for 12 to 14 months) of 2-month-old nulliparous or 8-month-old multiparous C3H/HeJ mice with 0.1 mg of 2-bromo-alpha-ergocryptine (CB-154) or 6-methyl-8-beta-ergoline-acetonitrile, efficacious inhibitors of prolactin secretion, markedly reduced the incidence of spontaneous mammary hyperplastic nodules and mammary tumors. CB-154 appeared to be more effective than 6-methyl-8-beta-ergoline-acetonitrile in suppressing the incidence of mammary tumors; the ergot virtually prevented the appearance of mammary tumors in nulliparous mice. Daily treatment of 5-month-old estrogen-treated, ovariectomized-hysterectomized C3H/HeJ mice for 12 months with CB-154 also significantly reduced the incidence of hyperplastic nodules and mammary tumors when compared with ovariectomized-hysterectomized mice treated with steroid alone. Daily treatment of multiparous C3H/HeJ mammary tumor-bearing mice with CB-154 or 6-methyl-8-beta-ergoline-acetonitrile generally failed, however, to promote regression of the mammary tumors. Thus significant prophylaxis of early preneoplastic lesions by drug-induced hormone (prolactin) suppression, resulting in a marked reduction in mammary tumor incidence, has been demonstrated in this study.
Assuntos
Bromocriptina/uso terapêutico , Ergolinas/uso terapêutico , Glândulas Mamárias Animais , Neoplasias Mamárias Experimentais/prevenção & controle , Lesões Pré-Cancerosas/prevenção & controle , Animais , Feminino , Hiperplasia/fisiopatologia , Hiperplasia/prevenção & controle , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metergolina/análogos & derivados , Camundongos , Camundongos Endogâmicos C3H , Paridade , Lesões Pré-Cancerosas/tratamento farmacológico , Prolactina/metabolismoRESUMO
Chronic suppression of prolactin by 2-bromo-alpha-ergocryptine (CB-154) in young nulliparous or mature multiparous C3H mice sharply suppressed the development of preneoplastic mammary gland lesions (hyperplastic alveolar nodules) and markedly inhibited the progression of these preneoplasias to carcinomas. This effect was also observed in C3H mice treated with either 17beta-estradiol or the oral contraceptive Enovid. Chronic CB-154 induced prolactin suppression was more effective than ovariectomy in the suppression of hyperplastic alveolar nodule development and comparable to ovariectomy in the suppression of mammary carcinoma development. Evidence is also provided indicating that human placental lactogen, a peptide chemically and physiologically similar to prolactin, promotes growth both in vitro (organ culture) and in vivo (athymic "nude" mouse) of the epithelium contained in benign human breast tumors. Whether or not human pituitary prolactin is capable of mimicking the mammotrophic action of human placental lactogen and whether a dysplastic, prolactin-sensitive lesion comparable to hyperplastic alveolar nodules exists in the human breast remains to be determined.
Assuntos
Neoplasias Mamárias Experimentais/etiologia , Lesões Pré-Cancerosas/etiologia , Prolactina/fisiologia , Animais , Neoplasias da Mama/metabolismo , Bromocriptina/farmacologia , Castração , DNA de Neoplasias/biossíntese , Estradiol/farmacologia , Feminino , Humanos , Neoplasias Mamárias Experimentais/prevenção & controle , Mestranol/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Nus , Transplante de Neoplasias , Noretinodrel/farmacologia , Técnicas de Cultura de Órgãos , Ovário/fisiologia , Paridade , Lactogênio Placentário/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , Gravidez , Prolactina/antagonistas & inibidores , Transplante HeterólogoRESUMO
Twenty biopsy specimens of benign human breast tumors obtained from 20 patients were processed into small slices and individually cultured for 2 days in Medium 199. The medium was supplemented with bovine insulin (5.0 microgram/ml), human placental lactogen (HPL) (10.0 microgram/ml), or ovine prolactin (10.0 microgram/ml). Four hr prior to termination, [3H]thymidine was added to the culture medium to determine DNA synthesis. The addition of insulin to the culture medium consistently increased: (a) the mean incorporation of [3H]thymidine into chemically extracted DNA (p less than 0.05); (b) the mean number of [3H]thymidine-radiolabeled epithelial cells (p less than 0.05), and (c) the mean number of epithelial cells bearing mitotic figures. The addition of HPL increased the mean number of [3H]thymidine-radiolabeled epithelial cells (p less than 0.05) and the mean number of epithelial cells bearing mitotic figures (p less than 0.05). [3H]Thymidine incorporation into chemically extracted DNA was also increased when HPL was added to the medium, although this increase did not quite achieve the 5% level of significance. The addition of ovine prolactin to the culture medium did not have any significant effect on DNA synthesis. This study provides evidence that insulin and HPL are direct stimulants of DNA synthesis of the epithelium contained in benign human breast tumors.
Assuntos
Neoplasias da Mama/metabolismo , DNA de Neoplasias/biossíntese , Insulina/farmacologia , Lactogênio Placentário/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Células Epiteliais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Mitose , Técnicas de Cultura de Órgãos , Gravidez , Prolactina/farmacologia , Timidina/metabolismoRESUMO
The effect of caffeine (430-500 mg/liter of drinking water) on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a chemically defined diet containing standard (5%) or high (20%) levels of fat (corn oil) was examined. In the initiation studies, caffeine and the standard or high fat diet treatments were provided for 34 days, from 24-29 days of age to 58-63 days of age. Three days prior to termination of caffeine-fat diet treatments, each rat received a single dose of DMBA. In the promotion studies, caffeine and the standard or high fat diets were provided commencing 3 days after a single dose of DMBA (at 56-61 days of age) and until termination of the study. Caffeine consumption, during the initiation phase significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat), in rats fed either a standard or high fat diet. In the promotion studies, prolonged consumption of caffeine in rats fed either a standard or high fat diet did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, an apparent increase in mammary carcinoma multiplicity was observed; this increase in mammary carcinoma multiplicity did not, however, reach the 5% level of statistical probability. When caffeine was administered during both the initiation and promotion phases, no significant effect on mammary carcinoma multiplicity was observed. Treatment of rats during the initiation or promotion phases with caffeinated coffee (via drinking water) mimicked the mammary tumor modulating activities of caffeine. Decaffeinated coffee consumption did not effect either the initiation or promotion phases of this tumorigenic process. In both the initiation and promotion studies, caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of mammary tumor appearance. Thus, in female rats fed a chemically defined standard or high fat diet, caffeine consumption can significantly influence chemical carcinogenesis of the mammary gland; an effect that is dependent upon the duration and time-span of caffeine administration.
Assuntos
Cafeína/toxicidade , Gorduras na Dieta/administração & dosagem , Gorduras Insaturadas/administração & dosagem , Neoplasias Mamárias Experimentais/induzido quimicamente , 9,10-Dimetil-1,2-benzantraceno , Animais , Peso Corporal/efeitos dos fármacos , Cocarcinogênese , Café/efeitos adversos , Feminino , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos EndogâmicosRESUMO
It is unequivocal that prolactin is an influential hormone in murine mammary tumorigenesis. The Berenblum hypothesis (7), a well-known theoretical model of tumorigenesis that depicts this oncogenic process as a two-step mechanism, i.e., initiation and promotion, is a conceptual scheme in which the action of prolactin in mammary tumorigenesis may be understood. According to this conceptual model, prolactin would participate in both the initiation and promotion steps of mammary tumorigenesis, In the initiation phase, variations in prolactin secretion appear to influence the metabolism of the mammary epithelium, so that the epithelium would be either more receptive to or refractory to an initiating agent (e.g., chemical carcinogen, physical carcinogens, oncogenic viruses, ets.) i.e., a permissive action. In the promotion phase, prolactin may act as either a promoter or an antipromoter of the "transformed" mammary epithelium. In promotion, the hormone may either directly or indirectly (via the ovary) stimulate mitotic activity of the "transformed" epithelium. In antipromotion the hormone, in the presence of requisite hormones (e.g., glucocorticoids), may synergistically induce differentiation (e.g., lactation) in the "transformed" epithelium. A tumor would result in the former (promotion) but not in the latter (antipromotion) case. Whether or not prolactin is significantly influential in human breast tumorigenesis remains to be determined. This is an extremely important area of research which is justifiably receiving increased attention. For if prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated prolactin suppression.
Assuntos
Neoplasias da Mama/etiologia , Neoplasias Mamárias Experimentais/etiologia , Prolactina/fisiologia , Glândulas Suprarrenais/fisiologia , Animais , Divisão Celular/efeitos dos fármacos , Estrogênios/farmacologia , Feminino , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Ovário/fisiologia , Hipófise/metabolismo , Hipófise/fisiologia , Lesões Pré-Cancerosas/etiologia , Gravidez , Prolactina/metabolismo , Prolactina/farmacologia , Ratos , Receptores de Superfície Celular , Receptores de EstrogênioRESUMO
Female Sprague-Dawley rats were treated at 53 days of age with a single intubation of 7,12-dimethylbenzanthracene (DMBA). Three days after carcinogen treatment, the animals were treated with retinyl acetate (RA) (at 3 dietary levels), hormone inhibition (HI) [tamoxifen (1-rho-beta-dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene) plus 2 bromo-alpha-ergocryptine], and/or immune stimulation (methanol-extracted residue of Bacillus Calmette-Guérin, cell wall skeleton of Nocardia rubra, or cell particulate of DMBA-induced rat mammary carcinomas plus Freund's complete adjuvant). RA at 0.6 or 1.0 mM concentrations per kg diet significantly reduced the incidence of mammary carcinomas; 0.2 mM concentrations of RA per kg diet did not affect tumor incidence. HI also significantly decreased mammary carcinoma incidence, an effect which was significantly enhanced by all 3 dietary levels of RA. Immune stimulation by methanol-extracted residue of Bacillus Calmette-Guérin or cell wall skeleton of Nocardia rubra did not affect mammary carcinoma incidence when administered either alone or in combination with RA and/or HI. The cell particulate of DMBA-induced rat mammary carcinomas plus Freund's complete adjuvant significantly reduced mammary carcinoma incidence in rats fed RA but did not affect mammary carcinoma incidence in placebo-fed rats or in rats treated only with HI. However, in rats treated with the triple combination of cell particulate of DMBA-induced rat mammary carcinomas plus Freund's complete adjuvant, RA, and HI, no mammary carcinomas were observed for the duration of treatment (20 weeks after DMBA administration). Although HI was always superior to RA feeding in the prophylaxis of this neoplastic process, a significant synergism between these two treatments was consistently observed. This distinct synergism was observed even when using the low dietary level of RA, an amount of RA which by itself was ineffective in the suppression of mammary carcinogenesis. With but one exception, immune stimulation did not significantly influence this carcinogenic process, either when administered alone or when administered to rats with a reduced mammary carcinoma burden, i.e., animals treated with RA and/or HI.
Assuntos
Bromocriptina/farmacologia , Neoplasias Mamárias Experimentais/fisiopatologia , Tamoxifeno/farmacologia , Vitamina A/análogos & derivados , 9,10-Dimetil-1,2-benzantraceno , Administração Oral , Animais , Divisão Celular/efeitos dos fármacos , Diterpenos , Feminino , Cinética , Neoplasias Mamárias Experimentais/imunologia , Mycobacterium bovis/imunologia , Nocardia/imunologia , Ratos , Ésteres de Retinil , Vitamina A/administração & dosagem , Vitamina A/farmacologiaRESUMO
Five biopsy specimens of morphologically normal human breast tissues, obtained from the margins of five benign human breast tumors, were processed into slices (4.0 x 4.0 x 0.1 mm) and transplanted s.c. dorsally (eight to ten slices/mouse) into forty-three 6- to 8-week-old female BALB/c athymic nude mice. Each individual human breast tissue specimen was transplanted into seven to ten mice. After 30 days, the mice were divided into four groups and treated for 30 days as follows: (a) controls receiving s.c. cholesterol pellets (38 mg); (b) estrogens that were administered in s.c. pellets containing 2 mg 17 beta-estradiol and 38 mg cholesterol and in drinking water containing 0.5 mg estrone per liter; (c) rat pituitary tumor (RPT), a cell suspension of MtT-W10 RPT that secretes large amounts of prolactin and growth hormone, injected dorsorostrally; and (d) RPT plus estrogens. Three to five human breast tissue grafts were removed from each mouse at the onset of treatment, and the remainder were removed at termination of treatment. DNA synthesis in the ductal epithelium was determined in pre- and posttreatment grafts by [3H]thymidine autoradiography after incubation of grafts for 4 hr in an isotope-enriched medium. The labeling index (LI), mean number of labeled epithelial cells per unit area of epithelial tissue, in pre- and posttreatment grafts was, respectively: (a) control, 7.6 +/- 1.4 and 7.1 +/- 1.4; (b) estrogens, 5.5 +/- 0.6 and 17.9 +/- 2.3; (c) RPT, 6.2 +/- 0.7 and 8.0 +/- 1.5; and (d) RPT plus estrogens, 6.3 +/- 0.8 and 26.6 +/- 2.5. A significant increase in LI was observed after treatment with estrogens (p less than 0.05) or RPT plus estrogen (p less than 0.001). Mean LI after treatment with RPT plus estrogens was significantly greater (p less than 0.02) than after estrogens alone. RPT alone did not significantly alter the LI. Thus, these results provide in vivo evidence that estrogens enhance DNA synthesis of the ductal epithelium of the normal human breast and that a growth factor (or factors) from RPT acts synergistically with estrogens to produce a more pronounced increase in DNA synthesis. RPT growth factors (perhaps prolactin and/or growth hormone) appear to require estrogens for DNA synthesis stimulation in normal human breast ductal epithelium.
Assuntos
DNA/biossíntese , Hormônios/administração & dosagem , Neoplasias Experimentais/metabolismo , Animais , Colesterol/administração & dosagem , Preparações de Ação Retardada , Epitélio/metabolismo , Estrogênios/administração & dosagem , Feminino , Hormônio do Crescimento/administração & dosagem , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Prolactina/administração & dosagemRESUMO
The effect of chronic caffeine consumption (500 mg/liter of drinking water) on the initiation and promotion stages of 7,12-dimethylbenz(a)anthracene (DMBA) (a low dose, 0.5 mg/100 g body weight, i.v.) and N-methyl-N-nitrosourea (MNU) (a standard dose, 2.5 mg/100 g body weight, i.v.) induced mammary gland tumorigenesis in female Sprague-Dawley rats was determined. In the initiation studies, caffeine was administered for 30 days prior to and for 3-4 days after carcinogen treatment (carcinogens administered at 55-57 days of age); in the promotion studies, caffeine was administered beginning 3-4 days after carcinogen treatment and until experiment termination (DMBA study and MNU study, 48 and 26 weeks after carcinogen treatment, respectively). In the DMBA study, there were 62-73 rats/group, in the MNU study, 40 rats/group. Eighty-nine % of the mammary tumors induced by DMBA were benign (adenomas, fibroadenomas, often with cystic secretory activity), 11% were carcinomas (intraductal and invasive); virtually all of the MNU-induced mammary tumors were carcinomas (approximately 99%). Caffeine consumption during the initiation stage in the DMBA-treated rats resulted in a significant decrease in the mean number of mammary carcinomas per rat (50% reduction, P less than 0.01) and mean number of benign mammary tumors per rat (28% reduction, P less than 0.05); caffeine consumption during the promotion stage significantly decreased the mean number of benign mammary tumors per rat (57% reduction, P less than 0.001) while not significantly influencing mammary carcinoma number. In contrast, caffeine consumption during either the initiation or promotion stages of MNU-treated rats did not significantly influence this tumorigenic process. The influence of caffeine on urinary and fecal excretion of tritiated DMBA and on rat mammary gland development at the time of carcinogen treatment also was determined. Slightly reduced levels of tritium in 24-h urinary samples were observed in caffeine-treated animals (P = 0.06). No significant effect of caffeine on 24- to 96-h fecal or 48- to 96-h urinary excretion of the isotope was observed. No apparent effect of caffeine on rat mammary gland development (number of ducts, degree of lobuloalveolar development) was observed. That caffeine significantly suppresses the initiation stage of DMBA-induced rat mammary gland tumorigenesis, while not influencing this stage when MNU is used as a carcinogen, suggests that caffeine acts via an alteration in carcinogen (DMBA) activation. The lack of a pronounced effect of caffeine on tritiated DMBA excretion, however, does cast some doubt on this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
9,10-Dimetil-1,2-benzantraceno/administração & dosagem , Cafeína/administração & dosagem , Neoplasias Mamárias Experimentais/induzido quimicamente , Metilnitrosoureia/administração & dosagem , 9,10-Dimetil-1,2-benzantraceno/farmacocinética , Animais , Carcinógenos , Sinergismo Farmacológico , Fezes/química , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos EndogâmicosRESUMO
The influence of lipids on gap-junction-mediated intercellular communication (i.e., metabolic cooperation) between Chinese hamster V79 cells was investigated. Unsaturated free fatty acids (oleate, linoleate, linolenate, palmitoleate, myristoleate, and arachidonate) inhibited metabolic cooperation between 6-thioguanine-resistant, hypoxanthine guanine phosphoribosyltransferase-deficient and 6-thioguanine-sensitive, hypoxanthine guanine phosphoribosyltransferase-proficient V79 cells. Saturated fatty acids (stearate, palmitate, myristate, and arachidate) had no effect. Further characterization of the effects of fatty acids on metabolic cooperation is summarized as follows: a relationship between the degree of unsaturation and the ability of unsaturated fatty acids to inhibit metabolic cooperation could not be established (i.e., inhibition of metabolic cooperation by 18:1 greater than 18:2 = 18:3); longer carbon chain monounsaturated fatty acids are more effective in inhibiting metabolic cooperation (i.e., inhibition of metabolic cooperation by 18:1 greater than 16:1 greater than or equal to 14:1); geometric isomerism is of some importance in determining the efficacy of monounsaturated fatty acids to inhibit metabolic cooperation (i.e., inhibition of metabolic cooperation by cis 18:1 greater than trans 18:1 and cis 16:1 greater than trans 16:1); and the position of the double bond(s) is relatively unimportant (i.e., inhibition of metabolic cooperation by 18:3 = gamma 18:3). Unsaturated diacylglycerol compounds (diolein, dilinolein, and 1-oleoyl-2-acetyl glycerol) inhibit metabolic cooperation; a saturated diacylglycerol compound (distearin) had no effect. The position of the unsaturated fatty acid groups is not of importance in the inhibition of metabolic cooperation by diacylglycerols containing unsaturated fatty acid moieties (i.e., 1,2-diolein and 1,3-diolein are equally efficacious in inhibiting metabolic cooperation; relative inhibition of metabolic cooperation by 18:1 greater than 1-oleoyl-2-acetyl glycerol greater than 1,2-diolein). Alterations of membrane biophysical properties and protein kinase C involvement are discussed as possible mechanisms involved in the inhibition of metabolic cooperation by unsaturated lipid.
Assuntos
Comunicação Celular/efeitos dos fármacos , Ácidos Graxos/farmacologia , Junções Intercelulares/fisiologia , Animais , Linhagem Celular , Cricetinae , Cricetulus , Diglicerídeos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Junções Intercelulares/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The purpose of this study was to determine whether or not the type of dietary fat can affect mammary gland growth processes in the immature and mature female BALB/c mouse. Groups of immature and mature mice were fed one of the following purified semisynthetic diets containing different types of fat, i.e., five vegetable oil diets (5% corn oil, 20% corn oil, 20% olive oil, 20% linseed oil, 19% coconut oil-1% corn oil); two animal fat diets (20% lard, 19% beef tallow-1% corn oil); and one fish oil diet (19% Menhaden oil-1% corn oil). In addition, fish-corn oil diets (20%) containing three different levels of corn oil (15%, 10%, 4.5%) and fish oil (5%, 10%, 15.5%) were also examined in these studies. Immature mice were fed these diets from 21 to 45 days of age, ovariectomized at 35 days of age, given injections daily of 17 beta-estradiol (1 microgram) and progesterone (1 mg) on Days 42 to 44, and sacrificed on Day 45. Mammary ductal expansion through the mammary fat-pad (mm, nipple to farthest end bud) was determined on the inguinal (No. 4) mammary glands. Mature mice were fed these diets from 28 to 128 days of age. Half of these mice were sacrificed between 118 and 128 days of age during the stage of estrus of the estrous cycle. The remaining half were given injections daily of 17 beta-estradiol (1 microgram) and progesterone (1 mg) from 118 to 127 days of age and sacrificed on Day 128. Mammary developmental growth was assessed on inguinal mammary glands by ascription of development scores, determination of epithelial area (mm2), and determination of total DNA levels. In both immature mice and mammotrophic hormone-treated mature mice fed the fish oil diet (19% Menhaden oil-1% corn oil, 15.5% Menhaden oil-4.5% corn oil), significantly (P less than 0.05) reduced developmental growth of the mammary gland was observed when compared to mice fed the 19 to 20% vegetable oil or animal fat diets. No significant difference in mammary gland developmental growth was observed among the groups of mice fed the 19 to 20% vegetable oil or animal fat diets. In immature mice and mammotrophic hormone-treated mature mice, significantly (P less than 0.05) reduced mammary gland developmental growth was observed in mice fed the 5% corn oil diet compared with mice fed the 20% corn oil diet. In mature mice not treated with exogenous mammotrophic hormones, no significant effect of diet on mammae development was observed.(ABSTRACT TRUNCATED AT 400 WORDS)