Correlation of MRI Biomarkers with Tumor Necrosis in Hras5 Tumor Xenograft in Athymic Rats

Magnetic resonance imaging (MRI) can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA) induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relation-ship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24) bearing 1.94 ± 0.2–cm3 subcutaneous Hras5 tumors (ATCC 41000) before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0–10 mg/kg, i.v.). We measured effective transverse relaxation rate (R2*), initial area under the gadolinium concentration–time curve (IAUGC60/150), equivalent enhancing fractions (EHF60/150), time con-stant (K trans), proportion of hypoperfused voxels as estimated from fit failures in K trans analysis, and signal intensity (SI) in T2-weighted MRI (T2W). ZD6126 treat-ment induced> 90 % dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evi-dent from T2W MRI. Although R2 * did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of> _ 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypo-perfused voxels might provide a useful biomarker of tumor necrosis