RESUMO
Tissue inhibitors of matrix metalloproteinase (TIMPs) are multifunctional proteins with both matrix metalloproteinase (MMP) inhibitory effects and growth-regulatory activity. TIMPs inhibit MMP activity, suggesting a use for cancer gene therapy. However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice. Consistent with tumor stimulation, TIMP-4 up-regulates Bcl-2 and Bcl-X(L) protein. TIMP-4 also inhibits apoptosis in human breast cancer cells in vitro and mammary tumors in vivo. A synthetic MMP inhibitor BB-94 did not have such antiapoptotic effect. Analysis of TIMP-4 expression in human mammary specimens indicates that TIMP-4 protein is increased in mammary carcinoma cells compared with normal mammary epithelial cells. These data indicate an antiapoptotic activity in breast cancer cells and a tumor-stimulating effect of TIMP-4 when administrated systemically.
Assuntos
Neoplasias da Mama/genética , Mama/fisiologia , Transformação Celular Neoplásica/genética , DNA/administração & dosagem , Inibidores Teciduais de Metaloproteinases/fisiologia , Animais , Apoptose/genética , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Sobrevivência Celular/genética , DNA/genética , Eletroporação , Feminino , Terapia Genética , Humanos , Injeções Intramusculares , Camundongos , Camundongos Nus , Transplante de Neoplasias , Plasmídeos/administração & dosagem , Plasmídeos/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Coelhos , Inibidores Teciduais de Metaloproteinases/biossíntese , Inibidores Teciduais de Metaloproteinases/genética , Transplante Heterólogo , Proteína bcl-X , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
Extracellular matrix (ECM) degrading matrix metalloproteinases (MMPs) lead to ECM turnover, a key event in cancer growth and progression. The tissue inhibitors of matrix metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use for cancer gene therapy. Here we report that systemic administration of naked TIMP-4 DNA significantly inhibited Wilms' tumor growth in nude mice. TIMP-4, whose expression was lost in Wilms' tumor, inhibited the growth of G401 Wilms' tumor cells at a concentration lower than those required for MMP inhibition. This inhibition was associated with internalization of exogenous recombinant TIMP-4. Electroporation-mediated intramuscular injection of TIMP-4 expression plasmid resulted in sustained plasma TIMP-4 levels and significant tumor suppression. Our data demonstrate a tumor suppressive effect of TIMP-4 against Wilms' tumor and the potential utility of intramuscular delivery of TIMP gene for treatment of kidney derived cancers.
Assuntos
Vacinas Anticâncer/farmacologia , Inibidores Teciduais de Metaloproteinases/genética , Vacinas de DNA/farmacologia , Tumor de Wilms/terapia , Adulto , Animais , Divisão Celular , Criança , Humanos , Injeções Intramusculares , Rim/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Nus , Plasmídeos , Inibidores Teciduais de Metaloproteinases/metabolismo , Inibidores Teciduais de Metaloproteinases/farmacologia , Células Tumorais Cultivadas , Tumor de Wilms/enzimologia , Tumor de Wilms/patologia , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
Here we present a case of severe B12 deficiency in an exclusively breastfed infant, born to a mother who had undergone gastric bypass 6 years earlier. At 4 months of age, the infant presented with pancytopenia and developmental delay. Our evaluation revealed physical and neurological developmental delay, pancytopenia with macrocytosis, with head imaging showing cortical and subcortical atrophy. Serum studies showed low B12, normal folate and iron. Treatment with parenteral B12 led to the resolution of the pancytopenia, steady weight gain and improved neurological status. The child is currently 16 months old with normal anthropometric and hematological parameters and normal B12 levels on a regular diet. Gross motor and speech developments are significantly delayed. This case illustrates that maternal B12 deficiency following gastric bypass surgery may lead to severe B12 deficiency with long-term neurological sequelae in their infants. Screening and prompt treatment of these deficiencies both during pregnancy and during infancy are important.
Assuntos
Aleitamento Materno/efeitos adversos , Derivação Gástrica/efeitos adversos , Complicações na Gravidez , Deficiência de Vitamina B 12/congênito , Feminino , Humanos , Lactente , Recém-Nascido , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Deficiência de Vitamina B 12/etiologiaRESUMO
Modulator is a novel low-molecular-weight organic compound that regulates activities of glucocorticoid and mineralocorticoid receptors as well as protein kinase C. In this study we show that male rat liver cytosolic estrogen receptor activation is inhibited by modulator in a dose-dependent manner. Fifty percent inhibition is obtained with 1 unit/ml modulator purified from bovine liver which is within the physiological concentration for modulator. However, sheep uterine cytosolic estrogen and androgen receptors are insensitive to regulation by modulator. Exogenous sodium molybdate treatment inhibits activation of all of these receptors of liver or uterus origin in an identical manner, further differentiating the effects of modulator and the molybdate anion.