RESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Oncologia/tendências , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina QuinasesRESUMO
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.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , Células-Tronco Neoplásicas/patologia , Adenoma/patologia , Animais , Transformação Celular Neoplásica/genética , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p57/biossíntese , Inibidor de Quinase Dependente de Ciclina p57/genética , DNA (Citosina-5-)-Metiltransferases/biossíntese , DNA Metiltransferase 3A , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Hibridização in Situ Fluorescente , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mucinas/biossíntese , Mucinas/genética , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/genética , Peptídeos/genética , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Fator Trefoil-2RESUMO
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.