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Modelos Animales de Enfermedad , Hemofilia A/patología , Animales , Densidad Ósea , Humanos , Masculino , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: The primary objective of this study was to evaluate the biochemical effects of gefitinib on its target signal-transduction pathways in patients with recurrent epithelial ovarian cancer (EOC). The secondary objectives included assessing clinical activity and toxicity and determining the association between biochemical and clinical outcomes. METHODS: Twenty-four heavily pretreated patients with EOC who had good end-organ function and performance status and who had measurable disease received gefitinib 500 mg daily. Prospectively planned core-needle tumor biopsies were obtained before treatment and after 4 weeks. Protein expression of total and phosphorylated (p) epidermal growth factor receptor (EGFR), protein kinase B (AKT), and extracellular regulated kinase (ERK) was quantified in microdissected tumor cells using tissue lysate array proteomics. RESULTS: All tumor samples had detectable levels of EGFR and p-EGFR. A decrease in the quantity of both EGFR and p-EGFR was observed with gefitinib therapy in >50% of patients. This was not associated with clinical benefit, nor were responses observed. However, trends for increased gastrointestinal and skin toxicity were observed with greater phosphorylation or quantities of EGFR, ERK, and AKT in tumor samples (P
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Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Adulto , Anciano , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Papilar/tratamiento farmacológico , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Gefitinib , Humanos , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fosforilación/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factores de Tiempo , Resultado del TratamientoRESUMEN
This study evaluated the effects of localized delivery of nitric oxide (NO) from hydrogels covalently modified with S-nitrosocysteine (Cys-NO) on neoinitma formation, a key component of restenosis, in a rat balloon-injury model. Soluble Cys-NO was used in preliminary studies to identify dosage ranges that were able to simultaneously inhibit smooth muscle cell proliferation, enhance endothelial cell proliferation, and reduce platelet adhesion. Photo-cross-linked PEG-based hydrogels were formed with covalently immobilized Cys-NO. These materials release NO for approximately 24 h and can be applied to tissues and photo-cross-linked in situ to form local drug-delivery systems. Localized delivery of NO from hydrogels containing Cys-NO inhibited neointima formation in a rat balloon-injury model by approximately 75% at 14 days.
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Cisteína/análogos & derivados , Células Endoteliales/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , S-Nitrosotioles/farmacología , Túnica Íntima/efectos de los fármacos , Angioplastia Coronaria con Balón , Animales , Arterias Carótidas/patología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , GMP Cíclico/biosíntesis , Cisteína/administración & dosificación , Cisteína/farmacología , Células Endoteliales/fisiología , Matriz Extracelular/metabolismo , Hidrogeles , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Donantes de Óxido Nítrico/administración & dosificación , Adhesividad Plaquetaria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , S-Nitrosotioles/administración & dosificación , Túnica Íntima/fisiologíaRESUMEN
Ovarian cancer is the leading cause of death from gynecologic malignancies among American women and the fourth most frequent cause of death from cancer in women in Europe and the US. Despite appropriate surgical and chemotherapeutic intervention, the 5-year survival in patients with metastatic cancer remains poor. Currently available screening methods, including CA125, additional biomarkers, and transvaginal ultrasound lack the necessary sensitivity and specificity to provide accurate and cost-efficient screening for the general population or the ability to assess who will benefit most from each treatment. These limitations have prompted the study of proteomic technology and its application in ovarian cancer diagnostics. Proteomics is the study of molecules in the functional protein pathways of normal or diseased states. Clinical trials are currently being conducted to assess the sensitivity and specificity of serum proteomic patterns and additional clinical trials are designed to evaluate the effects of molecularly targeted agents on protein signaling pathways in human subjects. Overcoming both scientific and practical limitations will lead to increased knowledge of deranged protein networks in cancer cells. Clinical trials in proteomics may result in improved early detection, better monitoring, new drugs and molecularly targeted therapeutics, and individualized therapies.
