RESUMO
BACKGROUND: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts. METHODS: Nude mice bearing human BRAF(V600D) WM266.4 melanoma or BRAF(V600E) Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis. RESULTS: Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls. CONCLUSION: Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies.
Assuntos
Benzimidazóis/farmacologia , Neoplasias do Colo/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética/métodos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Feminino , Humanos , Melanoma/enzimologia , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The radiation damping field induced by an intense NMR line can be counterbalanced by a DANTE sequence of small flip angle pulses of opposite phase applied during the free induction decay. The transient NMR signal is acquired, one complex data point at a time, in the intervals between these DANTE pulses. As the intense signal decays, reducing the radiation damping field, the flip angles of the DANTE pulses are reduced at a matching rate. An experimental test on an aqueous solution of d-glucose demonstrates a reduction in linewidth at half height from 13.5 to 0.8 Hz, revealing a weak doublet response previously hidden under the broad water line.
Assuntos
Glucose/efeitos da radiação , Espectroscopia de Ressonância Magnética/métodos , Água/química , Glucose/química , Processamento de Imagem Assistida por Computador , Magnetismo , Radiação não Ionizante , Sensibilidade e Especificidade , Soluções/química , Soluções/efeitos da radiaçãoRESUMO
A three-dimensional experiment is described in which NMR signals are separated according to their proton chemical shift, 13C chemical shift, and diffusion coefficient. The sequence is built up from a stimulated echo sequence with bipolar field gradient pulses and a conventional decoupled HMQC sequence. Results are presented for a model mixture of quinine, camphene, and geraniol in deuteriomethanol. Copyright 1998 Academic Press.
