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INTRODUCTION: The RCAS/tv-a transgenic system involves somatic gene transfer through infection by the avian leucosis virus (ALV-A) in mice expressing the gene for the RCAS receptor (tv-a). The nestin tv-a (Ntv-a) mouse, expresses tv-a under the control of the nestin promoter in glial-progenitors, and spontaneously develops glioma when infected with ALV-A that over-expresses PDGF. Using Ntv-a mice, we quantified response to Temozolomide (Tmz) treatment using T2-weighted anatomical imaging (T2w MRI), contrast-enhanced (CE) MRI, and diffusion MRI (DMRI). METHODS: 20 Ntv-a mice were divided into two groups: (1) vehicle control and (2) Tmz treated (p.o. qdx5). T2w MRI was used to measure tumor volume and delineate heterogeneities, and DMRI was used to measure tumor cellularity from the apparent diffusion coefficient (ADC) of water on day 0 (first day of treatment), and days 3, 7, 10, 14, then weekly thereafter. CE MRI was used to determine the extent of abnormal, ‘leaky’ vasculature on days 0, 7, 14, 21, then bi-weekly thereafter. The DMRI sequence used a navigator echo for motion correction, and shaped gradients for motion compensation and isotropic diffusion measurement, and all MRI incorporated contiguous 0.5mm thick transaxial slices to cover the entire tumor volume. Moribund mice were sacrificed and the brains harvested for histology. RESULTS AND DISCUSSION: Tumors were well delineated in T2w images, and showed features that were typical of human glioma (including solid tumor, necrosis, edema and cyst). Gliomas in mice treated with Tmz showed an early increase in the ADC (right panel of figure), and later a growth delay (middle panel of figure), and decrease in enhancing volume (left panels of figure), relative to vehicle control mice. Histology confirmed regions of decreased cellularity in treated tumors and the treated group of mice showed increased survival. CONCLUSION: We demonstrated a response to Tmz in ADC, tumor growth and the contrast-enhancing volume. These MRI-determined endpoints correlated with histology and survival. MRI methodology in the Ntv-a mouse may provide an efficient preclinical means for testing novel therapies, particularly for optimizing new combination strategies for treatment of glioma.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]