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A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.
Crawford, Shelby; Belajic, Daniel; Wei, Jianmei; Riley, Jason P; Dunford, Paul J; Bembenek, Scott; Fourie, Anne; Edwards, James P; Karlsson, Lars; Brunmark, Anders; Wolin, Ronald L; Blevitt, Jonathan M.
Afiliação
  • Crawford S; Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development LLC, La Jolla, CA 92121, USA.
Mol Cancer Ther ; 7(3): 492-9, 2008 Mar.
Article em En | MEDLINE | ID: mdl-18347137
ABSTRACT
B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Biomarcadores Tumorais / Interleucina-8 / Proteínas Proto-Oncogênicas B-raf / Melanoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Biomarcadores Tumorais / Interleucina-8 / Proteínas Proto-Oncogênicas B-raf / Melanoma Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article