RESUMEN
PURPOSE: The purpose of this study was to compare treatment outcomes between combined gonadotropin-releasing hormone agonist and tamoxifen (GnRHa+T) and sequential adriamycin and cyclophosphamide chemotherapy and tamoxifen (AC->T) in premenopausal patients with hormone-responsive, lymph-node-negative breast cancer. MATERIALS AND METHODS: In total, 994 premenopausal women with T1-T2, lymph-node-negative, hormone-receptor-positive, HER2-negative breast cancer between January 2003 and December 2008 were included in this retrospective cohort study. GnRHa+T and AC->T were administered to 608 patients (61.2%) and 386 patients (38.8%), respectively. Propensity score matching and inverse probability weighting were applied to the original cohort, and 260 patients for each treatment arm were included in the final analysis. Recurrence-free, cancer-specific, and overall survival was compared between the two treatment groups. RESULTS: A total of 994 patients were followed up for a median of 7.4 years (range, 0.5 to 11.4 years). The 5-year follow-up rate was 98.7%, and 13 patients were lost to follow-up. In propensity-matched cohorts (n=520), there was no difference in recurrence-free, cancer-specific, and overall survival rates between the two treatment groups (p=0.306, p=0.212, and p=0.102, respectively), and this was maintained after applying inverse probability weighting. CONCLUSION: GnRHa+T is a reasonable alternative to AC->T in patients with premenopausal, hormone-responsive, HER2-negative, lymph-node-negative, T1-T2 breast cancer.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Antineoplásicos Hormonales/agonistas , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Premenopausia , Receptor ErbB-2/genética , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
Androgen deprivation therapy is the cornerstone treatment for metastatic prostate cancer. It can be done either surgically or medically. Luteinizing hormone-releasing hormone agonists and antagonist are the most effective drugs, with different side effects and modes of action, but no clear efficacy differences. Adding a non-steroidal antiandrogen adds a marginal benefit but also significant side effects and costs. Non-steroidal antiandrogens should not be used as monotherapy. In most patients with metastases, immediate castration is the standard of care. The intermittent modality is apparently non-inferior to the continuous one, with some other benefits. Upfront chemotherapy added to castration should be considered as the new standard of care in many metastatic patients. Castration leads to many adverse effects, some potentially life-threatening such as cardiovascular side effects.
Asunto(s)
Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/efectos adversos , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/agonistas , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/prevención & control , Medicina Basada en la Evidencia , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Resultado del TratamientoRESUMEN
We report a case of diffuse endometrial squamous metaplasia found after in a resectoscopic myomectomy specimen. A 35-year-old woman underwent an office hysteroscopy that showed a submucosal leiomyoma. After pharmacologic treatment with a GnRH gonadotropin-releasing hormone agonists (GnRHa) leuprolide acetate, the patient underwent a resectoscopic myomectomy. Histologic examination showed fragments of myometrial tissue with the foci of endometrial glands with diffuse features of squamous metaplasia; in part classical, mature type; and in part immature type, and the so-called "morula type." Presence of endometrial squamous metaplasia in the endometrium may produce dramatic histologic changes on biopsies and sometimes it may be difficult to distinguish it from primitive primary carcinomas of nonendometrioid histology, representing therefore, a potential diagnostic pitfall. GnRHa therapy could play a possible role in the onset of squamous metaplasia. So the pathologist and gynecologist must take into account this possible metaplastic change for a correct clinicopathologic assessment and to avoid overtreatment.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Hiperplasia Endometrial/diagnóstico , Histerectomía , Metaplasia/complicaciones , Adulto , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/agonistas , Antineoplásicos Hormonales/uso terapéutico , Carcinoma de Células Escamosas/patología , Hiperplasia Endometrial/patología , Femenino , Hormona Liberadora de Gonadotropina/efectos adversos , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/uso terapéutico , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Humanos , Leiomioma/complicaciones , Leiomioma/tratamiento farmacológico , Leiomioma/patología , Metaplasia/patologíaRESUMEN
Gonadotropin-releasing hormone (GnRH) receptor activation has been demonstrated to inhibit cell proliferation in vitro and in vivo. These effects are dependent on the degree of receptor expression and the intracellular signaling protein milieu. The physiological and pathophysiological relevance is largely undefined, and its potential for exploitation in the treatment of specific malignancies is the subject of ongoing investigations. GnRH receptors are expressed in embryonic, juvenile and adult tissues, including brain, pituitary, gonads, accessory reproductive organs and placenta. The levels of receptor expression vary, from high in pituitary gonadotropes to low in peripheral tissues, although quantification of functional receptor protein has been determined in relatively few cell types. Roles for GnRH receptor signaling at different stages of animal development and its influence on reproductive health remain largely unexplored, except in cases of hereditary hypogonadal infertility. In addition to regulating hormone secretion, GnRH is postulated to act as a chemokine or a growth- and differentiation-inducing factor. Hence, receptor activation may influence the function of neuronal networks in the brain and the maturation of reproductive tissue epithelia. GnRH may also potentially influence the biology of cancerous cells in reproductive tissue since receptor activation may signal terminal differentiation, cell cycle arrest or apoptosis. In this context, the cell surface expression of GnRH receptor is important since it influences the intensity of intracellular signaling, and correlates with the ability to inhibit proliferation in transformed cells in vitro. Here, we review data on the effects of GnRH agonists on cell proliferation and apoptosis, and put forward hypotheses for investigation to determine whether the GnRH receptor acts as a tumor suppressor in neuroendocrine or epithelial cells.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Proliferación Celular/efectos de los fármacos , Hormona Liberadora de Gonadotropina/agonistas , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Animales , Antineoplásicos Hormonales/agonistas , Antineoplásicos Hormonales/farmacología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Ensayos Clínicos como Asunto , Regulación del Desarrollo de la Expresión Génica , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Modelos Biológicos , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Receptores LHRH/genética , Receptores LHRH/metabolismo , Transducción de Señal/genética , Distribución TisularRESUMEN
ICI182,780 (Fulvestrant) is a pure anti-estrogen used in adjuvant therapies of breast cancer. This compound not only inhibits the transcriptional activities of the estrogen receptor-alpha (ER alpha) but also induces its proteasome-dependent degradation. The latter activity is believed to be required for the antiproliferative effects of ICI182,780. Estrogen receptor-related receptor-alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily that is expressed in a wide range of tissues including breast tumors, in which its high expression correlates with poor prognosis. Although not regulated by any natural ligand, ERR alpha can be deactivated by the synthetic molecule XCT790. Here we demonstrate that this compound also induces a proteasome degradation of ERR alpha. We also show that although it does not act directly on the steady-state level of ER alpha, XCT790 potentiates the ICI182,780-induced ER alpha degradation. We suggest that treatment with XCT790 could thus enhance the efficacy of ICI182,780 in ER alpha-dependent pathologies such as breast cancer.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/metabolismo , Estradiol/análogos & derivados , Nitrilos/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Tiazoles/farmacología , Antineoplásicos Hormonales/agonistas , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Estradiol/agonistas , Estradiol/farmacología , Estradiol/uso terapéutico , Receptor alfa de Estrógeno/agonistas , Femenino , Fulvestrant , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Nitrilos/agonistas , Nitrilos/uso terapéutico , Pronóstico , Receptores de Estrógenos/agonistas , Tiazoles/agonistas , Tiazoles/uso terapéutico , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND AND SCOPE: Leuprorelin is a well known luteinising hormone releasing hormone (LHRH) agonist. The drug is effective in the treatment of advanced prostate cancer and is well tolerated. This article reviews published literature (based on a search of PubMed, EMBASE and Biosis databases to the end of 2005) and other sources of data on a new formulation of leuprorelin acetate (Eligard) for use in the treatment of hormone-dependent advanced prostate cancer. This product takes advantage of a novel delivery system (Atrigel) which forms an implant in situ that is capable of delivering double doses of leuprorelin consistently to provide better, more sustained testosterone suppression compared with a microsphere leuprolide acetate formulation. Two formulations, 7.5 mg and 22.5 mg, are currently available with duration of action of 1 and 3 months, respectively. The 2-week stability at room temperature prior to mixing facilitates its use and reduces the potential for waste. FINDINGS: In clinical studies of the new leuprorelin acetate formulation reviewed here, all patients achieved testosterone levels < or = 50 ng/dL and up to 98% of patients showed levels comparable to those resulting from surgical bilateral orchidectomy (< or = 20 ng/dL). Both formulations showed minimal breakthroughs, defined as a rise in testosterone levels after reaching levels of 50 ng/dL. The safety profile is typical of LHRH agonists, with mild to moderately severe 'hot flushes' being the most common adverse event. The higher dose of 22.5 mg, with a volume of 0.375 mL is administered subcutaneously via a small 20G needle, causing little local discomfort. CONCLUSION: Prostate cancer remains a major cause of morbidity and mortality in older men. In the majority of cases, suppression of serum testosterone levels is very effective. The level of testosterone suppression is currently under debate, with ideal suppression levels ranging from 20 to 50 ng/dL. Not all LHRH agonist therapy achieves the same degree of testosterone suppression as bilateral orchidectomy. The new leuprorelin acetate (Eligard) appears to achieve a testosterone suppression of 20 ng/dL in 98% of patients, while maintaining a side effect profile comparable to other products in its class.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Leuprolida/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/agonistas , Preparaciones de Acción Retardada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Leuprolida/administración & dosificación , Leuprolida/análogos & derivados , Masculino , Neoplasias de la Próstata/fisiopatología , Testosterona/antagonistas & inhibidores , Testosterona/sangreRESUMEN
The antiestrogen tamoxifen has been widely used for decades as selective estrogen receptor (ER) modulator for ERalpha-positive breast tumors. Tamoxifen significantly reduces tumor recurrence by binding to the activation function-2 (AF-2) domain of the ER. Acquired resistance to tamoxifen in breast cancer patients is a serious therapeutic problem. Antiestrogen-resistant breast cancer often shows increased expression of the epidermal growth factor receptor (EGFR) family members, EGFR and ErbB2. In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ERalpha, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen. In contrast, transfection of activated MAPK kinase, an immediate upstream activator of MAPK (ERK 1 and 2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ERalpha, inhibition of ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen. Inhibition of AKT by short inhibitory RNA blocked Ser167 phosphorylation in ER and restored tamoxifen sensitivity. However, maximum sensitivity to tamoxifen was observed when both AKT and MAPK were inhibited. Taken together, these data demonstrate that different phosphorylation sites in the AF-1 domain of ERalpha regulate the agonistic and antagonistic actions of tamoxifen in human breast cancer cells.
Asunto(s)
Antineoplásicos Hormonales/agonistas , Antineoplásicos Hormonales/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Tamoxifeno/agonistas , Tamoxifeno/antagonistas & inhibidores , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/antagonistas & inhibidores , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Oncogénicas v-erbB/metabolismo , Fosforilación , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Serina/metabolismo , Tamoxifeno/uso terapéutico , TransfecciónRESUMEN
The aim of this study was to explore the pharmacological response to 4-hydroxy-tamoxifen (OH-Tam) and to estradiol (E2) in three cell lines: MVLN, a human breast carcinoma cell line derived from MCF-7, and two MVLN-derived OH-Tam-resistant (OTR) cell lines, called CL6.8 and CL6.32. The OH-Tam response in the OTR cells was associated with the development of both an agonist activity of the drug on cell proliferation and the resistance of the cells to OH-Tam-induced apoptosis. The OTR cells also developed an increased sensitivity to the E2 growth-stimulating activity. To delineate the genes that determine such responses, we combined a mini-array-based gene-selection approach and an extensive real-time quantitative PCR exploration in the MVLN and OTR cell lines exposed to three pharmacological conditions: a 4-day treatment with E2, OH-Tam or both E2 and OH-Tam. Compiled data revealed a hyper-response to E2 and a modification of the OH-Tam pharmacological response (loss of antagonist action and agonist activity) at the gene-expression level. The proteins encoded by the genes selected in this study have been reported to be involved in the regulation of cell proliferation, cell transformation, DNA repair and apoptosis, or belong to the ErbB/epidermal growth factor receptor-driven pathway. Our data also provide evidence of changes in transcriptional co-regulator expression, elevated mitogen-activated protein kinase activity and increase in the phosphorylation status of estrogen receptor alpha on serine residue 118 in the OTR cell lines, suggesting the possible involvement of such mechanisms in the agonist activity of OH-Tam and/or the hyper-response of cells to E2. Taken together, our study should enhance our knowledge of the multifactorial events associated with the development of Tam resistance in two independent cell lines issued from the same selection process and should help in the identification of potential molecular targets for diagnosis or therapy.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Estradiol/uso terapéutico , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapéutico , Antineoplásicos Hormonales/agonistas , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Ciclo Celular/efectos de los fármacos , Quimioterapia Combinada , Femenino , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Tamoxifeno/agonistas , Células Tumorales CultivadasRESUMEN
Hepatocellular carcinoma (HCC) is characterized by high drug resistance to currently available chemotherapeutic agents. In a prospective clinical study, we have demonstrated that high-dose tamoxifen significantly enhanced the therapeutic efficacy of doxorubicin in patients with far-advanced HCC. In a search for a possible mechanism, we found that tamoxifen at a clinically achievable concentration (2.5 microM) significantly enhanced doxorubicin-induced cytotoxicity and apoptosis of Hep-3B cells, a multidrug resistance (MDR)-1 expressing HCC cell line. This synergistic cytotoxic effect of tamoxifen, at this concentration, however, was not mediated by MDR inhibition. Instead, as evidenced by both western blot and immunofluorescence studies, tamoxifen inhibited the cytoplasmic-membrane translocation of protein kinase C (PKC)-alpha. 12-O-Tetradecanoylphorbol-13-acetate (TPA) restored the membrane translocation of PKC-alpha and abrogated the synergistic cytotoxicity of tamoxifen. We also showed that tamoxifen, at this concentration, did not directly affect the enzyme activity of PKC. Further, membrane translocation of other membrane-bound proteins, such as Ras protein, was similarly inhibited by tamoxifen, but could not be restored by the addition of TPA. Together, these data suggested that tamoxifen may act on the cytoplasmic membrane, and thereby inhibit PKC-alpha translocation to the membrane where it is activated. We hypothesize that high-dose tamoxifen may be an effective modulator of doxorubicin in the treatment of HCC, and suggest that biochemical modulation of PKC as a measure to improve systemic chemotherapy for HCC deserves further investigation.