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1.
Cancer Res ; 66(7): 3611-9, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16585186

RESUMO

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Ovarianas/enzimologia , Neoplasias da Próstata/enzimologia , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/farmacologia , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Clonagem Molecular , Feminino , Humanos , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Invasividade Neoplásica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Inibidores de Serina Proteinase/imunologia
2.
Cancer Res ; 65(18): 8397-405, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16166318

RESUMO

Gene expression analysis showed that a human mindin homologue, mindin/RG-1, is expressed selectively in prostate tissues and that its expression level is elevated in some prostate tumors. Mindin/RG-1 protein expression is maintained in >80% of prostate cancers metastatic to bone or lymph nodes as well as in locally recurrent tumors in androgen-unresponsive patients. In contrast, mindin/RG-1 expression in other normal tissues is significantly lower than that seen in the prostate. A fully human antibody, 19G9, was generated against mindin/RG-1 protein and was shown to accumulate at high abundance in LNCaP tumor xenografts. Conjugates of this antibody with the chelator CHX-A''-DTPA were generated and radiolabeled with either 111In, 90Y, or 86Y. Small animal positron emission tomography imaging with the 86Y-radiolabeled conjugate showed very specific accumulation of the antibody in LNCaP tumor xenografts with clear tumor delineation apparent at 4 hours. The therapeutic efficacy of [90Y]-CHX-A''-DTPA-19G9 was evaluated in mice bearing LNCaP xenografts. A dose-finding study identified a nontoxic therapeutic dose to be approximately 75 microCi. Significant antitumor effects were seen with a single administration of radiolabeled antibody to animals bearing 200 to 400 mm3 tumors. Inhibition of tumor growth was observed in all treated animals over a 49-day period. At 49 days posttreatment, slow tumor growth recurred but this could be prevented for an additional 40-day period by a second administration of a 75 microCi dose at day 49. We conclude that [90Y]-CHX-A''-DTPA-19G9 is a novel antibody conjugate that has considerable promise for therapy of metastatic prostate cancer in androgen-unresponsive patients.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas da Matriz Extracelular/imunologia , Imunotoxinas/imunologia , Neoplasias da Próstata/radioterapia , Radioimunoterapia/métodos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Especificidade de Anticorpos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Células CHO , Cricetinae , Relação Dose-Resposta Imunológica , Proteínas da Matriz Extracelular/biossíntese , Proteínas da Matriz Extracelular/genética , Humanos , Imunotoxinas/farmacocinética , Imunotoxinas/farmacologia , Isotiocianatos/imunologia , Isotiocianatos/farmacocinética , Isotiocianatos/farmacologia , Masculino , Dados de Sequência Molecular , Ácido Pentético/análogos & derivados , Ácido Pentético/imunologia , Ácido Pentético/farmacocinética , Ácido Pentético/farmacologia , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/farmacocinética , Radioisótopos de Ítrio/farmacologia
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