RESUMO
BACKGROUND AND METHODS: Gene therapy may offer a new tool for the treatment of renal cell carcinoma (RCC). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild-type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) and endostatin (ES) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus-mediated marker gene transfers (GFP) were used as controls. RESULTS: In vivo transduction efficiency, measured using GFP gene transfer, was 27+/-7%. The combination gene therapy with HSV-tk and ES adenoviruses resulted in a significant antitumor effect (P<.01) compared to single HSV-tk (n.s.) or ES (n.s.). In the survival study, all tumors with single gene therapy using HSV-tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated (57%). Survival of these mice equaled healthy nude mice, and was significantly prolonged (P<.0001) compared to HSV-tk (P<.028) and ES (n.s.) groups. CONCLUSIONS: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV-tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.
Assuntos
Carcinoma de Células Renais/terapia , Colágeno/genética , Terapia Genética/métodos , Neoplasias Renais/terapia , Fragmentos de Peptídeos/genética , Simplexvirus/genética , Timidina Quinase/genética , Sequência de Aminoácidos , Animais , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Endostatinas , Glioma , Proteínas de Fluorescência Verde , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Proteínas Luminescentes/genética , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/uso terapêutico , Simplexvirus/enzimologia , Timidina Quinase/uso terapêutico , Fatores de Tempo , Transplante Heterólogo , Células Tumorais CultivadasAssuntos
Receptores Imunológicos/química , Receptores Imunológicos/metabolismo , Adenoviridae/genética , Animais , Bovinos , LDL-Colesterol/metabolismo , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática , Técnicas de Transferência de Genes , Hormônio do Crescimento/química , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Ligantes , Camundongos , Reação em Cadeia da Polimerase , Sinais Direcionadores de Proteínas , Receptores Imunológicos/genética , Receptores Imunológicos/uso terapêutico , Receptores Depuradores , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , SolubilidadeRESUMO
Atherosclerosis is a multifactorial disease that involves several genes and proteins. The purpose of this article is to focus on the arterial wall and to review lipoprotein receptors, growth factors, cytokines, chemokines, matrix metalloproteinases, adhesion molecules, and apoptosis genes and their involvement in atherogenesis.
Assuntos
Arteriosclerose/genética , Expressão Gênica , Apoptose/genética , Moléculas de Adesão Celular/genética , Citocinas/genética , Substâncias de Crescimento/genética , Humanos , Fatores de Transcrição/genéticaRESUMO
We have constructed a novel fusion protein "Scavidin" consisting of the macrophage scavenger receptor class A and avidin. The Scavidin fusion protein is transported to plasma membranes where the avidin portion of the fusion protein binds biotin with high affinity and forms the basis for the targeted delivery of biotinylated molecules. Subcellular fractionation analysis, immunostaining, and electron microscopy demonstrated endosomal localization of the fusion protein. According to pulse-labeling and cross-linking studies Scavidin is found as monomers (55 kDa), dimers, and multimers, of which the 220-kDa form was the most abundant. The biotin binding capacity and active endocytosis of the biotinylated ligands were demonstrated in rat malignant glioma. Local Scavidin gene transfer to target tissues could have general utility as a universal tool to deliver biotinylated molecules at systemic low concentrations for therapeutic and imaging purposes, whereby high local concentration is achieved.