RESUMEN
The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Antiinfecciosos/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Linfocitos T CD8-positivos/inmunología , Pirimetamina/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Femenino , Humanos , Proteínas de Membrana de los Lisosomas/genética , Proteínas de Membrana de los Lisosomas/metabolismo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Pirimetamina/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Escape del Tumor , Estados UnidosRESUMEN
Studies show the delivery of inhaled medications is maximized when a metered-dose inhaler (MDI) with a spacer is utilized. Our residents expressed concern with their knowledge of MDIs and spacers. This study was designed to address those concerns. Residents were given a 12-question pre-intervention, self-assessment questionnaire that explored their overall knowledge and comfort in utilizing MDI with spacers. Participants then received educational intervention via multimedia videos and a demonstration of proper use of MDI with spacer. Participants were given the same questionnaire immediately following the education and again 3 months later. Improvement was significant (P < .05) for each element studied as derived from the 12 questions. Improvement remained significant when these variables were assessed in the 3-month follow-up. In this study, we successfully improved the ability of our residents to deliver quality care by improving their knowledge and confidence in utilizing MDIs with spacers.