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Tumor Biology 18: Animal Models of Human Cancers 3: Central Nervous System and Imaging

Abstract #2756

Efficacy of temozolomide in a transgenic model of glioma: MRI determined tumor growth inhibition and diffusion response are predictive of survival

MIR Preclinical Services, Inc., Ann Arbor, MI and Memorial Sloan Kettering Cancer Center, New York, NY

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 by MRI determination of tumor growth and apparent diffusion coefficient (ADC), and survival. METHODS: Tumored Ntv-a mice were divided into two groups: (1) vehicle control (n=12) and (2) TMZ treated (n=13; 100 mg/kg qdx5 ip). T2w MRI was used to monitor tumor growth and diffusion MRI (DMRI) was used to characterize cell kill from tissue ADC before treatment, and 3, 7, 10, and 14 days after treatment, and weekly thereafter. Survival was also determined. 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). A robust early increase in ADC (day 3) was observed, that correlated with growth inhibition and survival. CONCLUSION: TMZ produces growth inhibition and increase in median survival, and an early increase in ADC in the tv-a transgenic mouse model of glioma. MRI methodology in the Ntv-a mouse provides an efficient means for preclinical drug testing. DMRI provided an early indication of efficacy and has the potential to be used for high throughput therapeutic screening in this model.