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1.
Life Sci ; 142: 66-75, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26477293

RESUMEN

AIMS: Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. MAIN METHODS: To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1mg·kg(-1) per day, i.p., for 5days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in lung explants supernatants were measured and interferon gamma (IFN-γ) in bronchiolar lavage cells suspensions (BAL) was measured. KEY FINDINGS: The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-α and IFN-γ expression. SIGNIFICANCE: Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients.


Asunto(s)
Asma/inmunología , Hiperprolactinemia/inmunología , Pulmón/inmunología , Animales , Asma/sangre , Asma/inducido químicamente , Asma/patología , Citocinas/sangre , Citocinas/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Hiperprolactinemia/sangre , Hiperprolactinemia/inducido químicamente , Hiperprolactinemia/patología , Inflamación/sangre , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Prolactina/toxicidad , Ratas , Ratas Wistar , Factores de Tiempo
2.
J Clin Invest ; 122(10): 3791-5, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23006326

RESUMEN

Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists.


Asunto(s)
Anovulación/tratamiento farmacológico , Hiperprolactinemia/tratamiento farmacológico , Kisspeptinas/uso terapéutico , Animales , Anovulación/etiología , Anovulación/fisiopatología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ciclo Estral/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hormona Liberadora de Gonadotropina/metabolismo , Gonadotropinas Hipofisarias/biosíntesis , Gonadotropinas Hipofisarias/sangre , Gonadotropinas Hipofisarias/metabolismo , Hiperprolactinemia/inducido químicamente , Hiperprolactinemia/complicaciones , Hiperprolactinemia/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Bombas de Infusión Implantables , Kisspeptinas/biosíntesis , Kisspeptinas/genética , Masculino , Ratones , Prolactina/administración & dosificación , Prolactina/toxicidad , Flujo Pulsátil , ARN Mensajero/biosíntesis , ARN Mensajero/genética
3.
Artículo en Inglés | MEDLINE | ID: mdl-17570137

RESUMEN

Observations associated with drug-induced hyper- or hypoprolactinemia in rat toxicology studies may be similar and include increased ovarian weight due to increased presence of corpora lutea. Hyperprolactinemia may be distinguished if mammary gland hyperplasia with secretion and/or vaginal mucification is observed. Reproductive toxicity study endpoints can differentiate hyper- from hypoprolactinemia based on their differential effects on estrous cycles, mating, and fertility. Although the manifestations of hyper- and hypoprolactinemia in rats generally differ from that in humans, mechanisms of drug-related changes in prolactin synthesis/release can be conserved across species and pathologically increased or decreased prolactin levels may compromise some aspect of reproductive function in all species.


Asunto(s)
Prolactina/deficiencia , Prolactina/toxicidad , Reproducción/efectos de los fármacos , Animales , Femenino , Hiperprolactinemia/sangre , Prolactina/sangre , Ratas , Pruebas de Toxicidad Crónica/métodos
4.
J Appl Toxicol ; 25(3): 179-83, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15856525

RESUMEN

Prolactin-induced mammary carcinogenesis in rodents, particularly rats, is often stated to be of low toxicological relevance to humans. This opinion appears to have developed from a number of lines of cited evidence. Firstly, there had been long experience of use of dopamine antagonists (that increase prolactin) in human medicine and no evidence of an increase in breast cancer incidence or risk had been reported. Secondly, dopamine agonists (that lower prolactin) had been shown to have no effect in human breast cancer treatment. Thirdly, the actions of prolactin were considered different between rodents and humans. However, recent evidence now suggests that prolactin has a major role in human breast cancer, and the similarity of mechanism with the rodent suggests that prolactin-mediated mammary carcinogenesis in rodents could be of much higher toxicological relevance to humans than previously thought. Large epidemiology studies have upgraded a limited database and shown that dopamine antagonists (both antipsychotics and anti-emetics) increase breast cancer risk, that hyperprolactinaemia is consistently associated with human breast cancer growth, development and poor prognosis, and that prolactin is indeed a mitogen in human breast cancer cells that suppresses apoptosis and upregulates BRCA1. It is now clear that initial studies giving dopamine agonists to breast cancer patients had no effect because breast cancer cells also produced prolactin independently of the pituitary, which remained uncontrolled and unrecognized in early clinical studies. The evidence for the role of prolactin in human breast cancer is now strong and consistent, and is discussed and related to the risk assessment of drugs and chemicals. The conclusion is that it is invalid to suggest that prolactin-induced mammary carcinogenesis in rodents is of low relevance to humans because prolactin can induce an adverse response in the mammary tissue of both rodents and humans alike. Drugs and chemicals causing rodent prolactin-induced mammary carcinogenesis may therefore pose a risk to humans via the same mechanism if exposures also increase prolactin secretion in humans.


Asunto(s)
Neoplasias de la Mama/inducido químicamente , Antagonistas de Dopamina/efectos adversos , Neoplasias Mamarias Experimentales/inducido químicamente , Prolactina/efectos adversos , Animales , Femenino , Humanos , Ratones , Persona de Mediana Edad , Posmenopausia , Prolactina/toxicidad , Ratas , Medición de Riesgo
5.
Clin Cancer Res ; 5(11): 3583-93, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10589775

RESUMEN

Human breast cancer is the predominant malignancy and the leading cause of cancer death in women from Western societies. The cause of breast cancer is still unknown. Recently, the association between human prolactin (hPRL) activity and breast cancer has been reemphasized. Biologically active hPRL has been found to be produced locally by breast cancer cells that contain high levels of PRL receptor. A high incidence of mammary tumor growth has also been found in transgenic mice overexpressing lactogenic hormones. More importantly, it has been demonstrated that the receptors for sex steroids and PRL are coexpressed and cross-regulated. In this study, we report that we have designed and produced a hPRL antagonist, hPRL-G129R. By using cell proliferation assays, we have demonstrated that: (a) hPRL and E2 exhibited an additive stimulatory effect on human breast cancer cell (T-47D) proliferation; (b) hPRL-G129R possessed an inhibitory effect on T-47D cell proliferation; and (c) when antiestrogen (4-OH-tamoxifen) and anti-PRL (hPRL-G129R) agents were added together, an additive inhibitory effect was observed. We further investigated the mechanism of the inhibitory effects of hPRL-G129R in four hPRLR positive breast cancer cell lines. We report that hPRL-G129R is able to induce apoptosis in all four cell lines in a dose-dependent manner as determined by the Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The apoptosis is induced within 2 h of treatment at a dose as low as 50 ng/ml. We hope that the hPRL antagonist could be used to improve the outcome of human breast cancer therapy in the near future.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Moduladores de los Receptores de Estrógeno/toxicidad , Antagonistas de Hormonas/toxicidad , Prolactina/antagonistas & inhibidores , Prolactina/toxicidad , Secuencia de Aminoácidos , Animales , Técnicas de Cocultivo , Interacciones Farmacológicas , Femenino , Humanos , Etiquetado Corte-Fin in Situ , Células L , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Prolactina/química , Estructura Secundaria de Proteína , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Tamoxifeno/análogos & derivados , Tamoxifeno/toxicidad , Células Tumorales Cultivadas , Vertebrados
6.
Artículo en Inglés | MEDLINE | ID: mdl-3298106

RESUMEN

The importance of the promotion stage and of the physiological condition of target cells at the time of initiation is illustrated in both the rat mammary carcinogenesis and the mouse T-cell lymphomagenesis. In the former, prolactin was shown to be a powerful promoter regardless of the initiating agent. Prolactin was also found to be useful in detecting the carcinogenicity of the small doses of carcinogens; a high r.b.e. of 2.0 MeV fission spectrum neutrons was demonstrated by the application of prolactin to radiation-initiated mammary carcinogenesis in rats. In the latter, total-body irradiation involving both bone marrow and thymus facilitates chemically-initiated T-cell lymphomagenesis in mice. This could be attributed to the amplification of the cell population susceptible to a chemical carcinogen in the target tissue during the recovery phase after irradiation. The dual effect of a carcinogen, acting in the different phases of carcinogenesis was suggested by the split administration of N-nitrosoethylurea (NEU) in the induction of T-cell lymphomas. It is emphasized, through these findings, that besides the initiation by a genotoxic agent, the availability of a promoter or an inhibitor determines the fate of initiated cells, and that a modifier of target cells also plays a crucial role in the efficient induction of a tumour.


Asunto(s)
Cocarcinogénesis , Leucemia Inducida por Radiación , Linfoma/etiología , Neoplasias Mamarias Experimentales/etiología , Neoplasias Inducidas por Radiación , Prolactina/toxicidad , Animales , Etilnitrosourea , Femenino , Linfoma/inducido químicamente , Neoplasias Mamarias Experimentales/inducido químicamente , Ratones , Ratas , Linfocitos T
7.
Mol Cell Endocrinol ; 46(3): 245-52, 1986 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3017783

RESUMEN

Conjugates of ovine prolactin and daunomycin were prepared for use as affinity-labelled drug carriers in cancer cells carrying the prolactin receptor. The binding affinity of the conjugates to prolactin receptors in rat liver membrane preparations and in viable granulosa cells derived from estradiol- and pregnant mare serum gonadotropin (PMSG)-treated immature female rats was less than an order of magnitude lower than prolactin. The toxicity of the conjugate in cultured granulosa cells was dependent upon the concentration of the daunomycin present in the culture. The cytotoxic effect of the ligand was abolished by the addition of free prolactin or NH4Cl to the granulosa cell cultures. These conjugates may be useful probes in drug targeting against hormone-sensitive cancer.


Asunto(s)
Daunorrubicina/análogos & derivados , Células de la Granulosa/metabolismo , Prolactina/análogos & derivados , Receptores de Superficie Celular/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Daunorrubicina/administración & dosificación , Daunorrubicina/metabolismo , Daunorrubicina/toxicidad , Femenino , Células de la Granulosa/efectos de los fármacos , Cinética , Ligandos , Progesterona/biosíntesis , Prolactina/administración & dosificación , Prolactina/metabolismo , Prolactina/toxicidad , Ratas , Ratas Endogámicas , Receptores de Prolactina , Espectrometría de Fluorescencia
9.
J Natl Cancer Inst ; 57(5): 1057-62, 1976 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-187788

RESUMEN

Newborn female mice of three strains--BALB/cfC3H [mammary tumor virus (MuMTV)-infected], BALB/c, and C57BL (both virus-free)--were given injections of 17beta-estradiol or testosterone, alone or in combination with ovine prolactin, for the first 5 days of life. Half of each group of mice were ovariectomized at 40 days of age, and all mice were killed between 6 and 16 months of age. Mammary glands of BALB/cfC3H mice receiving steroid hormones were better developed than those of mice not receiving steroids. Androgen induced a higher incidence of grossly dilated ducts and secretion-filled alveoli. Mammary nodule and tumor incidences were higher in steroid-treated mice than in controls; androgen resulted in higher incidences than did estrogen. The age of onset of mammary tumors was also earlier after neonatal steroid treatment. In BALB/c mice, neonatal injections of estrogen induced some alveolar development of the mammary gland; neonatal injections of ovine prolactin had a greater effect. The mammary glands of C57BL mice did not show any evidence of stimulation by neonatal hormone treatment, which indicated the probability of strain differences. However, no nodules or tumors occurred in these MuMTV-free strains. Therefore, MuMTV was essential for neoplastic mammary responses to neonatal hormone treatment. Ovariectomy prevented alveolar development and abnormal changes in the mammary glands of all groups, thus indicating that ovary-independent alterations in the mammary gland were not induced by neonatal steroid treatment. We concluded that neonatal steroid exposure resulted in increased mammary tumor risk in mice, but only in the presence of both MuMTV and ovaries.


Asunto(s)
Animales Recién Nacidos , Estradiol/farmacología , Estradiol/toxicidad , Glándulas Mamarias Animales/efectos de los fármacos , Neoplasias Mamarias Experimentales/inducido químicamente , Prolactina/farmacología , Prolactina/toxicidad , Testosterona/farmacología , Animales , Castración , Femenino , Glándulas Mamarias Animales/crecimiento & desarrollo , Virus del Tumor Mamario del Ratón , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ovario/fisiología , Especificidad de la Especie , Factores de Tiempo
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