RESUMEN
Kinase inhibitors are now among the most important drugs in targeted therapy and are used in particular for the treatment of different tumor entities. Since many kinase inhibitors inhibit various tyrosine kinases efficiently but not specifically, they are often characterized by their versatile use in a wide variety of entities and diseases. The diverse use of this group of drugs, as well as the challenge of their side-effect profile, continues to make kinase inhibitors the subject of numerous clinical studies. The following article provides an overview of recent new approvals in the field of kinase inhibitors and shows their importance for oncological therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Oncología Médica/tendencias , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/patología , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina QuinasasRESUMEN
Aberrant de novo methylation of DNA is considered an important mediator of tumorigenesis. To investigate the role of de novo DNA methyltransferase 3a (Dnmt3a) in intestinal tumor development, we analyzed the expression of Dnmt3a in murine colon crypts, murine colon adenomas and human colorectal cancer using RNA fluorescence in situ hybridization (FISH), quantitative PCR and immunostaining. Following conditional deletion of Dnmt3a in the colon of APC((Min/+)) mice, we analyzed tumor numbers, genotype of macroadenomas and laser dissected microadenomas, global and regional DNA methylation and gene expression. Our results showed increased Dnmt3a expression in colon adenomas of APC((Min/+)) mice and human colorectal cancer samples when compared with control tissue. Interestingly, in tumor tissue, RNA FISH analysis showed highest Dnmt3a expression in Lgr5-positive stem/progenitor cells. Deletion of Dnmt3a in APC((Min/+)) mice reduced colon tumor numbers by ~40%. Remaining adenomas and microadenomas almost exclusively contained the non-recombined Dnmt3a allele; no tumors composed of the inactivated Dnmt3a allele were detected. DNA methylation was reduced at the Oct4, Nanog, Tff2 and Cdkn1c promoters and expression of the tumor-suppressor genes Tff2 and Cdkn1c was increased. In conclusion, our results show that Dnmt3a is predominantly expressed in the stem/progenitor cell compartment of tumors and that deletion of Dnmt3a inhibits the earliest stages of intestinal tumor development.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN/genética , Células Madre Neoplásicas/patología , Adenoma/patología , Animales , Transformación Celular Neoplásica/genética , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/patología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , ADN Metiltransferasa 3A , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Hibridación Fluorescente in Situ , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mucinas/biosíntesis , Mucinas/genética , Proteínas Musculares/biosíntesis , Proteínas Musculares/genética , Proteína Homeótica Nanog , Factor 3 de Transcripción de Unión a Octámeros/genética , Péptidos/genética , Regiones Promotoras Genéticas , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor Trefoil-2RESUMEN
The following conceptual framework formed the basis for a common decision made by the health ministers of Germany's 16 federal states to set up an influenza pandemic preparedness plan. The worst case scenario was used, on the basis of the data from the pandemic of 'Spanish flu', in 1918-20. The priority groups for vaccination were assessed, as well as the potentially available antiviral treatments. National policies could be highly improved by a common European view.