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1.
Ann Oncol ; 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-39306585

RESUMEN

BACKGROUND: Pembrolizumab significantly improved overall survival (OS) versus ipilimumab for unresectable advanced melanoma in KEYNOTE-006 (NCT01866319); 10-year follow-up data are presented. PATIENTS AND METHODS: Patients with unresectable stage III or IV melanoma were randomly assigned (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 weeks or every 3 weeks for ≤2 years (pooled), or ipilimumab 3 mg/kg i.v. every 3 weeks for four cycles. After KEYNOTE-006, patients could transition to KEYNOTE-587 (NCT03486873) for long-term follow-up. Eligible patients could receive second-course pembrolizumab. The primary endpoint was OS; modified progression-free survival (PFS; censored at date last known alive), modified PFS on second-course pembrolizumab, and melanoma-specific survival were exploratory. RESULTS: Of 834 patients randomly assigned in KEYNOTE-006 (pembrolizumab, n = 556; ipilimumab, n = 278), 333 (39.9%) were eligible for KEYNOTE-587; 211/333 patients (25.3%) transitioned to KEYNOTE-587 (pembrolizumab, n = 159; ipilimumab, n = 52) and 122 (14.6%) did not. For patients who transitioned to KEYNOTE-587 (n = 211), median time from randomization in KEYNOTE-006 to data cut-off for KEYNOTE-587 (1 May 2024) was 123.7 months (range, 122.0-127.3 months). Median OS was 32.7 months [95% confidence interval (CI) 24.5-41.6 months] for pembrolizumab and 15.9 months (95% CI 13.3-22.0 months) for ipilimumab [hazard ratio (HR), 0.71 (95% CI 0.60-0.85)]; 10-year OS was 34.0% and 23.6%, respectively. Among patients who completed ≥94 weeks of pembrolizumab, median OS from week 94 was not reached (NR; 95% CI NR-NR); 8-year OS rate was 80.8%. Median modified PFS was 9.4 months (95% CI 6.7-11.6 months) for pembrolizumab and 3.8 months (2.9-4.3 months) for ipilimumab [HR, 0.64 (95% CI 0.54-0.75)]. Among patients who received second-course pembrolizumab, median modified PFS from start of second course was 51.8 months (95% CI 11.0 months-NR); 6-year modified PFS was 49.2%. Median melanoma-specific survival was 51.9 months (95% CI 30.0-114.7 months) for pembrolizumab and 17.2 months (13.9-25.9 months) for ipilimumab [HR, 0.66 (95% CI 0.55-0.81)]. CONCLUSIONS: These results confirm that pembrolizumab provides long-term survival benefits in advanced melanoma, supporting it as a standard of care in this setting.

2.
Ann Oncol ; 31(4): 532-540, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32147213

RESUMEN

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.


Asunto(s)
Interleucina-12 , Melanoma , Neoplasias Cutáneas , Electroporación , Humanos , Inmunidad , Interleucina-12/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Plásmidos , Estudios Prospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética
3.
Br J Cancer ; 112(8): 1326-31, 2015 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-25867272

RESUMEN

BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Axitinib , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Didesoxinucleósidos , Femenino , Humanos , Imidazoles/efectos adversos , Indazoles/efectos adversos , Masculino , Melanoma/diagnóstico por imagen , Melanoma/genética , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Radiografía , Resultado del Tratamiento
4.
Br J Cancer ; 106(1): 85-91, 2012 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-22127285

RESUMEN

BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia , Familia-src Quinasas/antagonistas & inhibidores , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dacarbazina/efectos adversos , Dasatinib , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Pirimidinas/efectos adversos , Análisis de Supervivencia , Tiazoles/efectos adversos , Resultado del Tratamiento
5.
Cancer Chemother Pharmacol ; 67(3): 657-66, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20509027

RESUMEN

PURPOSE: High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma. METHODS: For PK analysis, 32 patients received peginterferon α-2b 6 µg/(kg week) subcutaneously for 8 weeks (induction) then 3 µg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied. RESULTS: Peginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision. CONCLUSIONS: Peginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity.


Asunto(s)
Interferón-alfa/farmacología , Melanoma/tratamiento farmacológico , Modelos Biológicos , Polietilenglicoles/farmacología , Adulto , Anciano , Quimioterapia Adyuvante/métodos , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Inyecciones Subcutáneas , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacocinética , Masculino , Melanoma/patología , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Estudios Prospectivos , Proteínas Recombinantes , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
6.
Br J Cancer ; 103(10): 1548-53, 2010 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-20924376

RESUMEN

BACKGROUND: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. METHODS: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). CONCLUSION: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.


Asunto(s)
Benzotiazoles/toxicidad , Benzotiazoles/uso terapéutico , Epotilonas/toxicidad , Epotilonas/uso terapéutico , Melanoma/tratamiento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Benzotiazoles/farmacocinética , Progresión de la Enfermedad , Epotilonas/farmacocinética , Femenino , Semivida , Humanos , Masculino , Melanoma/patología , Melanoma/radioterapia , Melanoma/cirugía , Metástasis de la Neoplasia , Estadificación de Neoplasias , Estudios Prospectivos , Medición de Riesgo , Resultado del Tratamiento , Moduladores de Tubulina/uso terapéutico , Moduladores de Tubulina/toxicidad
7.
Parasitology ; 122 Pt 1: 111-20, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11197759

RESUMEN

The cuticle is a major barrier prohibiting the infection of nematodes against micro-organisms. The attachment of bacterial spores of the nematode hyperparasite Pasteuria penetrans (PP1) to field populations of root-knot nematodes (RKN, Meloidogyne spp.) from Burkino Faso, Ecuador, Greece, Malawi, Senegal and Trinidad and Tobago were assayed in standard attachment tests. The attachment of spore population PP1 to different field populations of root-knot nematode showed that the rates of attachment differed between countries. Similar tests were also undertaken on P. penetrans spores from these countries against 2 species of RKN, M. incognita and M. arenaria. The results showed a high degree of variability in spore attachment with no clear distinction between the 2 species of nematode. It has been hypothesized that Pasteuria spore attachment is linked to nematode species designations and this study clearly shows that this is not the case. Further tests showed that variation in spore attachment was not linked to nematode phylogeny. The results therefore beg the question of how do parthenogenetic root-knot nematodes maintain cuticle variability in the face of such an aggressive hyperparasite.


Asunto(s)
Adhesión Bacteriana , Bacterias Grampositivas Formadoras de Endosporas/fisiología , Tylenchoidea/microbiología , Animales , Burkina Faso , Análisis por Conglomerados , Ecuador , Grecia , Malaui , Filogenia , Raíces de Plantas/parasitología , Senegal , Esporas Bacterianas/fisiología , Trinidad y Tobago , Tylenchoidea/clasificación
8.
Cell Biol Int ; 23(4): 299-306, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10600238

RESUMEN

A 35-kDa protein (designated p35) showing antigenic homology with an N-terminal epitope on the SV-40 large T-antigen oncoprotein was purified from transformed cardiomyocytes. Sequence analysis of several tryptic peptides indicated that p35 was not homologous to previously described sequences. Polyclonal antibody raised against synthetic peptide containing one of the tryptic fragments was used in Western blot analyses to ascertain the tissue-specific pattern of p35 expression. p35 was expressed ubiquitously in adult mouse tissues, and was detected in both embryonic and transformed cardiomyocyte preparations. Subcellular fractionation studies indicated that p35 is an integral membrane protein. Expression of p35 appeared to be regulated by growth conditions as evidenced by a transient decrease in protein levels following the addition of serum to quiescent NIH 3T3 cells.


Asunto(s)
Proteínas de la Membrana/aislamiento & purificación , Miocardio/química , Células 3T3 , Animales , Antígenos Virales de Tumores , Western Blotting , Transformación Celular Neoplásica , Células Cultivadas , Bases de Datos Factuales , Perros , Epítopos/química , Proteínas de la Membrana/química , Ratones , Ratones Transgénicos , Miocardio/citología , Miocardio/metabolismo , Mapeo Peptídico/métodos , Homología de Secuencia de Aminoácido , Virus 40 de los Simios
9.
J Biol Chem ; 271(46): 29255-64, 1996 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-8910585

RESUMEN

Previous studies have identified a 180-kDa mouse cardiomyocyte phosphoprotein with limited epitopic homology to p53. In this study, the protein was purified and partially sequenced. Oligonucleotide probes based on the available amino acid sequence data were used to isolate cDNA clones. Sequence analyses revealed that the clones encoded a protein with regional homology to the yeast RAD50 gene product. Expression of the mouse cDNA rescued the methyl methanesulfonate-sensitive phenotype in rad50 mutant yeast, indicating that the cardiomyocyte phosphoprotein is the mammalian homologue of the yeast RAD50 gene product. Fluorescence in situ hybridization analyses localized the mouse RAD50 gene to the A5-B1 region of chromosome 11. Northern blot analyses demonstrated a complex pattern of RAD50 expression during mouse development which was further complicated by the presence of several alternatively spliced transcripts. High levels of RAD50 expression was evident in the adult myocardium, a somewhat surprising observation given the absence of DNA synthesis in adult cardiomyocytes.


Asunto(s)
Proteínas de Unión al ADN , Epítopos/genética , Proteínas Fúngicas/inmunología , Miocardio/metabolismo , Proteínas de Saccharomyces cerevisiae , Proteína p53 Supresora de Tumor/inmunología , Células 3T3 , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Complementario , Proteínas Fúngicas/genética , Ratones , Ratones Endogámicos C3H , Datos de Secuencia Molecular , Miocardio/citología , Homología de Secuencia de Aminoácido
10.
Ann N Y Acad Sci ; 752: 446-54, 1995 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-7755290

RESUMEN

Cardiomyocytes in the adult mammal retain little or none of their developmental capacity for hyperplastic growth. As a consequence of this differentiated, nonproliferative phenotype, cardiomyocyte loss due to injury or disease is irreversible. Therapeutic intervention in end-stage diseased hearts is currently limited to cardiac transplantation. An increase in cardiomyocyte number in diseased hearts could improve function. Augmentation of the cardiomyocyte population may be achievable by the expression of regulatory proteins in the myocardium, or by intracardiac grafting of exogenous cardiomyocytes.


Asunto(s)
Corazón/fisiología , Miocardio/citología , Regeneración , Animales , Diferenciación Celular , División Celular , Expresión Génica , Cardiopatías/terapia , Humanos , Hiperplasia , Mamíferos , Miocardio/metabolismo
11.
J Biol Chem ; 269(36): 22607-13, 1994 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-8077211

RESUMEN

Previous studies have identified several host proteins (p53, p107, and p193), which form prominent complexes with SV40 T antigen in transformed cardiomyocytes. Expression of p53 and p107 was monitored during normal and pathologic growth in nontransformed murine myocardium. Both genes were expressed at relatively high levels in embryonic cardiomyocytes. Transcript levels decreased markedly during the process of cardiomyocyte terminal differentiation and were very low or undetectable in adult animals. In contrast, retinoblastoma transcripts were observed at low levels throughout myocardial development. None of the tumor suppressor genes examined were transcriptionally activated during acute myocardial overload or isoproterenol-induced myocardial hypertrophy. The potential role of tumor suppressor gene product expression in myocardial development and pathology is discussed.


Asunto(s)
Cardiomegalia/metabolismo , Expresión Génica , Genes Supresores de Tumor , Miocardio/metabolismo , Animales , Antígenos Transformadores de Poliomavirus/biosíntesis , Northern Blotting , Western Blotting , Peso Corporal , Cardiomegalia/inducido químicamente , Línea Celular Transformada , Células Cultivadas , Expresión Génica/efectos de los fármacos , Genes Supresores de Tumor/efectos de los fármacos , Células HeLa , Corazón/efectos de los fármacos , Humanos , Isoproterenol/toxicidad , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Tamaño de los Órganos , Valores de Referencia , Proteína de Retinoblastoma/biosíntesis , Virus 40 de los Simios/genética , Transcripción Genética , Proteína p53 Supresora de Tumor/biosíntesis
12.
Am J Physiol ; 264(5 Pt 2): H1693-700, 1993 May.
Artículo en Inglés | MEDLINE | ID: mdl-8498581

RESUMEN

A cell line derived from transgenic mice expressing the SV40 large T-antigen oncogene in the heart was used to identify cardiomyocyte targets for T-antigen binding. A novel protein of molecular mass of 193 kDa was identified as an associated protein by virtue of its ability to be co-immunoprecipitated with multiple anti-T-antigen antibodies. Two previously described proteins, p120 and p53, were also observed to complex with T-antigen in transformed cardiomyocytes. In addition, several proteins that cross-reacted with either anti-T-antigen or anti-p53 antibodies were identified. Two of these proteins, of apparent molecular masses of 250 and 110 kDa, were only observed in cardiomyocytes. Expression of a third cross-reacting protein of a molecular mass of 180 kDa appeared to be dependent on the growth status of the cells. These proteins may be important constituents of the cardiomyocyte cell cycle, as well as potential cellular targets for myocardial regeneration.


Asunto(s)
Antígenos Transformadores de Poliomavirus/metabolismo , Miocardio/metabolismo , Proteínas/metabolismo , Animales , Anticuerpos Monoclonales , Antígenos Transformadores de Poliomavirus/genética , Línea Celular , Reacciones Cruzadas , Ratones , Ratones Transgénicos , Pruebas de Precipitina , Proteína p53 Supresora de Tumor/metabolismo
13.
Am J Physiol ; 262(6 Pt 2): H1867-76, 1992 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1377879

RESUMEN

To determine the proliferative potential of adult ventricular cardiomyocytes, we have generated transgenic mice that express the SV40 large T-antigen oncogene in the heart. A fusion gene comprised of the rat alpha-cardiac myosin heavy chain promoter and the SV40 early region was used to target oncogene expression to the myocardium. Expression of SV40 large T-antigen was observed in both atrial and ventricular cardiomyocytes in adult transgenic animals. T-antigen expression was associated with hyperplasia in the targeted cells. Immunohistological analysis indicated that the proliferating cells continued to express sarcomeric myosin. Electron microscopic examination demonstrated that cardiomyocytes in various stages of the cell cycle retained ultrastructural characteristics typical of mitotic cardiac muscle cells in vivo. Cardiomyocytes isolated from transgenic tumors were able to proliferate in culture and retained a differentiated phenotype, as evidenced by spontaneous contractile activity. Preliminary studies indicate that these cells can undergo a limited number of passages while retaining this differentiated phenotype. These studies demonstrate that both ventricular and atrial cardiomyocytes from transgenic mice proliferate in response to targeted T-antigen expression.


Asunto(s)
Expresión Génica , Miocardio/metabolismo , Miosinas/genética , Virus 40 de los Simios/genética , Animales , Secuencia de Bases , Western Blotting , División Celular , Clonación Molecular , Neoplasias Cardíacas/patología , Inmunohistoquímica/métodos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Miocardio/patología , Miocardio/ultraestructura , Miosinas/química , Sondas de Oligonucleótidos/genética , Coloración y Etiquetado
14.
Endocrinology ; 126(6): 2927-35, 1990 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2161740

RESUMEN

Ovarian angiotensin I (Ang I)-converting enzyme (ACE), estimated by the specific binding of the ACE inhibitor [125I]iodo-MK-351A, is localized on multiple ovarian structures, including follicular granulosa cells, corpora lutea, terminal epithelium, and ovarian blood vessels, but total ovarian ACE does not display a cyclic pattern of variation during the rat estrous cycle. We have previously shown that ACE is localized on the granulosa cell layer of a subpopulation of rat ovarian follicles. Our present study shows that ovarian granulosa cells contain high affinity [binding site affinity (Kd), approximately 90 pM] and low capacity [binding site density (Bmax), approximately 12 fmol/2.5 X 10(5) cells] [125I]iodo-MK-351A-binding sites and convert [125I]iodo-Ang I to [125I]iodo-Ang II (greater than 85% of this conversion was inhibited by the ACE inhibitor captopril). Throughout the rat estrous cycle, 94-100% of developing follicles and 89-96% of atretic follicles contained high levels of ACE; however, ACE was either not observed or its levels were very low in preovulatory follicles. These findings indicate the presence of high levels of biologically active ACE on the surface of granulosa cells and suggest a potential role for follicular ACE in early stages of follicular maturation and atresia. Although ACE is known to process a variety of peptides found within the ovary, and these peptides may have opposing effects on follicular maturation, we attempted to define the cumulative effect of ACE inhibition on follicular maturation. Short and long term (6- and 14-day) infusions of captopril (6-day, 30.5 +/- 3.5 ova; 14-day, 28.5 +/- 7.5 ova) in immature rats, in which ovulation was induced by sequential treatments with PMSG and hCG, did not significantly affect ovulation compared with that in vehicle-infused control rats (6-day, 22.4 +/- 2.4 ova; 14-day, 20.8 +/- 3.1 ova), suggesting that ACE inhibition does not modify the follicular selection process in a way that affects ovulation. This may explain the lack of any reports of adverse effects of clinically used ACE inhibitors on ovulation.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Estro/fisiología , Folículo Ovárico/enzimología , Ovario/enzimología , Ovulación/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , 1-Sarcosina-8-Isoleucina Angiotensina II/metabolismo , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animales , Sitios de Unión , Captopril/farmacología , Membrana Celular/enzimología , Gonadotropina Coriónica/metabolismo , Dipéptidos/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Células de la Granulosa/enzimología , Radioisótopos de Yodo , Ratas , Ratas Endogámicas
15.
Endocrinology ; 122(6): 2727-34, 1988 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3131122

RESUMEN

Ovarian angiotensin II (Ang II) receptors display a cyclical pattern of variation during the rat estrous cycle. Ang II receptors, estimated by the specific binding of the Ang II receptor antagonist [125I]iodo-[Sar1,Ile8] Ang II to ovarian membranes, were lowest at estrus [binding site density (Bmax) = 35 +/- 2 fmol/mg; binding site affinity (KD) = 2.0 +/- 0.2 nM] and highest at diestrus I (Bmax = 59 +/- 3 fmol/mg; KD = 1.6 +/- 0.1 nM). We have previously shown that Ang II receptors in the rat ovary predominantly exist on the granulosa cell layer of a subpopulation of follicles. Our present studies show that the Ang II receptor-containing follicles in the rat ovary are mainly atretic (approximately 80%) or show signs of early atresia (approximately 15%) during all stages of the estrous cycle. A small number of Ang II receptor-containing follicles were healthy (approximately 5%). In contrast to the Ang II receptor-containing follicles, the FSH receptor-containing follicles were predominantly healthy (greater than 90%). Follicles which contained both Ang II receptors and FSH receptors were mainly early atretic. Since Ang II receptor-containing follicles in the rat ovary were mainly atretic these studies suggest that in the rat Ang II may be a major factor in regulating the function of atretic ovarian follicles.


Asunto(s)
Angiotensina II/metabolismo , Estro/metabolismo , Atresia Folicular , Fase Folicular , Ovario/metabolismo , Receptores de Angiotensina/metabolismo , 1-Sarcosina-8-Isoleucina Angiotensina II/metabolismo , Animales , Membrana Celular/metabolismo , Epitelio/metabolismo , Femenino , Hormona Folículo Estimulante/metabolismo , Radioisótopos de Yodo , Folículo Ovárico/anatomía & histología , Folículo Ovárico/metabolismo , Ratas , Ratas Endogámicas , Receptores de HFE/metabolismo , Distribución Tisular
16.
Am J Med Sci ; 295(4): 406-8, 1988 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3284358

RESUMEN

Mammalian ovarian follicles contain the enzymes and prohormones necessary to elaborate the active octapeptide hormone angiotensin II. In the rat ovary, angiotensin II receptors are located primarily in the theca interna and granulosa cell layers of a discrete subpopulation of follicles. Angiotensin II stimulates both androgen and estrogen secretion from rat ovarian slices. These findings suggest an autocrine/paracrine role for angiotensin II in ovarian follicular development.


Asunto(s)
Angiotensina II/fisiología , Folículo Ovárico/fisiología , Ovario/fisiología , Andrógenos/metabolismo , Animales , Estrógenos/metabolismo , Femenino , Ovario/metabolismo , Sistema Renina-Angiotensina
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