Imaging hypoxia in xenografted and murine tumors with 18F-fluoroazomycin arabinoside:: A comparative study involving micropet, autoradiography, Po2-polarography, and fluorescence microscopy

Purpose: Positron emission tomography (PET) allows noninvasive assessment of tumor hypoxia; however the combination of low resolution and slow tracer clearance from nonhypoxic tissue is problematic. The aim of this study was to examine the in vivo hypoxia selectivity of fluoroazomycin arabinoside ([F-18]-FAZA), a promising tracer with improved washout kinetics from oxygenated tissue. Methods and Materials: Three squamous cell carcinomas and one fibrosarcoma with widely differing spatial patterns of vascularization, hypoxia, and necrosis were grown in mice and evaluated with PET and complementary methods. Results: Eppendorf electrode measurements consistently demonstrated median Po-2 values <1 mm Hg. In accordance with that, PET revealed that all tumors accumulated [F-18]-FAZA in excess of reference tissue. Next the two-dimensional spatial distribution of [F-18]-FAZA (from autoradiography) was compared with fluorescence images of the same tumor sections showing localization of the hypoxia marker pimonidazole and the perfusion marker Hoechst 33342. Pixel-by-pixel analysis of co-registered images showed a highly significant co-localization between the two hypoxia markers and an inverse correlation (except for the fibrosarcoma) between the distribution of [F-18]-FAZA and Hoechst dye. Moreover intratumoral heterogeneity in tracer distribution was clearly visible on autoradiograms with a [F-18]-FAZA concentration approximately six times higher in poorly oxygenated areas than in vascular hot spots. Conclusions: The distribution of [F-18]-FAZA is consistent with hypoxia as the key driving force for tracer tissue retention in a selection of tumors with widely differing physiology. (C) 2008 Elsevier Inc.