RESUMEN
We have previously reported that superoxide stimulates the motility of tumor cells and the administration of Cu-Zn superoxide dismutase (SOD) significantly suppresses metastasis. However, ideally, anti-metastatic therapy should be long-lasting, systemically effective and have low toxicity. The half-life of Cu-Zn SOD in plasma is so short that it cannot provide long-lasting effects. Therefore, in this study we have developed a gene therapy in a mouse model utilizing extracellular SOD (EC-SOD), which is the most prevalent SOD isoenzyme in extracellular fluids. We retrovirally transfected fibroblasts (syngeneic) with the EC-SOD gene and established EC-SOD-secreting fibroblasts. Inoculation of EC-SOD-secreting fibroblasts suppressed both artificial and spontaneous metastatic lung nodules in mouse metastasis models. These data indicate the feasibility of anti-metastatic gene therapy utilizing the EC-SOD gene.
Asunto(s)
Terapia Genética/métodos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Superóxido Dismutasa/genética , Transducción Genética , Animales , Carcinoma Pulmonar de Lewis/patología , Carcinoma Pulmonar de Lewis/secundario , Carcinoma Pulmonar de Lewis/terapia , Técnicas de Cultivo de Célula , División Celular , Medios de Cultivo , ADN Complementario/genética , Estudios de Factibilidad , Fibroblastos/trasplante , Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Trasplante de Neoplasias , ARN Mensajero/genética , Sarcoma Experimental/patología , Sarcoma Experimental/secundario , Sarcoma Experimental/terapia , Superóxido Dismutasa/metabolismoRESUMEN
Acute graft-versus-host diseases (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). T helper 1 (Th1)-type cytokines such as interferon-gamma or tumor necrosis factor-alpha have been implicated in the pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative, which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study was designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates lethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not only the production of Th1-type cytokines, but also the proportion of Th1 cells in CD4(+) helper T cells in this GVHD mouse model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.