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1.
IDrugs ; 9(12): 849-53, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17139572

RESUMO

Early-phase clinical trials have traditionally focused on the safety, tolerability and pharmacokinetic properties of a therapeutic candidate, while questions regarding efficacy have been left unanswered until phase II clinical development. Although an understanding of all of these parameters is unarguably essential to the successful development of a drug candidate, this information is insufficient. Biomarkers are increasingly being used in early drug development to allow for the exploration of pharmacodynamic effects of targeted therapeutics before clinical signs and symptoms are evaluated. The trend of using pharmacodynamic biomarkers will continue and, ultimately, may enable these biomarkers to be used routinely to demonstrate the impact of a compound on the treatment of a disease, and to aid in the selection of therapeutic doses and regimens based on accurate measures of human physiological responses. Biomarkers are also beginning to be used to determine those patients who are most likely to respond to a therapeutic, and thereby improve treatment outcomes while avoiding the administration of a drug to individuals who are unlikely to benefit. This article describes a strategy that is being used to achieve these aims for biomarkers, and discusses how biomarkers can be used to identify information that can be applied back into to the drug discovery process.


Assuntos
Biomarcadores/análise , Farmacologia/tendências , Avaliação Pré-Clínica de Medicamentos , Humanos , Informática Médica
2.
Genomics ; 86(6): 648-56, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16297596

RESUMO

Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.


Assuntos
Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , LDL-Colesterol/metabolismo , Variação Genética , Proteínas de Membrana/genética , Negro ou Afro-Americano/genética , Ezetimiba , Frequência do Gene , Hispânico ou Latino/genética , Humanos , Absorção Intestinal/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Fitosteróis/sangue , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estados Unidos , População Branca/genética
3.
Mol Cancer Ther ; 4(3): 413-25, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15767550

RESUMO

Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cells. Inhibition of KDR catalytic activity blocks tumor neoangiogenesis, reduces vascular permeability, and, in animal models, inhibits tumor growth and metastasis. Using a gene expression profiling strategy in rat tumor models, we identified a set of six genes that are selectively overexpressed in tumor endothelial cells relative to tumor cells and whose pattern of expression correlates with the rate of tumor endothelial cell proliferation. In addition to being potential targets for antiangiogenesis tumor therapy, the expression patterns of these genes or their protein products may aid the development of pharmacodynamic assays for small molecule inhibitors of the KDR kinase in human tumors.


Assuntos
Biomarcadores Tumorais , Perfilação da Expressão Gênica/métodos , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Primers do DNA/química , Células Endoteliais/citologia , Endotélio Vascular/citologia , Humanos , Imuno-Histoquímica , Microcirculação/citologia , Microscopia de Fluorescência , Metástase Neoplásica , Transplante de Neoplasias , Neovascularização Patológica , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Virology ; 306(2): 371-5, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12642109

RESUMO

Transduction of T cells with a chimeric immune T cell receptor (CIR) has been proposed as a strategy to generate cellular immunity against viral pathogens such as HIV-1. In the case of the CD4-CD3-zeta chain (CD4-zeta) CIR, specificity for HIV-1 is conferred by binding of the CD4 moiety to gp120 on the surface of infected cells. However, it is unclear whether CD4-zeta-T cells may differ from naturally derived CD8(+) cytotoxic T cells (CTL) in their susceptibility to viral escape mechanisms or ability to recognize different cell types that support viral replication. We demonstrate that CIR-T cells can mediate antiviral activity against HIV-1 in cells that are resistant to class I-restricted CTL-mediated activity. Furthermore, CIR-T cells can suppress virus in multiple cell types, including monocytes, dendritic cells, and lymphocyte-dendritic cell clusters. These results provide evidence that T cells can be redirected against novel targets, and that independence from the class I pathway may have distinct advantages.


Assuntos
Infecções por HIV/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T Citotóxicos/imunologia , Complexo CD3/genética , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Células Dendríticas/imunologia , Células Dendríticas/virologia , Terapia Genética , Infecções por HIV/terapia , HIV-1/imunologia , HIV-1/fisiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Celular , Imunoterapia , Monócitos/imunologia , Monócitos/virologia , Receptores Imunológicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Transdução Genética , Replicação Viral
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