Tumor hypoxia, present in many human
cancers, can lead to resistance to radiation and
chemotherapy, is associated with a more aggressive
tumor phenotype and is an independent prognostic factor of clinical outcome. It is therefore important to identify and localize tumor hypoxia in
cancer patients. In the current study, serial microPET imaging was used to evaluate
iodine-124-labeled iodo-azomycin-galactoside ((124)I-IAZG) (4.2-day physical half-life) as a
hypoxia imaging agent in 17 MCa
breast tumors and six FSaII
fibrosarcomas implanted in mice. For comparison, another promising hypoxic-cell PET radiotracer, fluorine-18-labeled fluoro-
misonidazole ((18)F-FMISO), was also imaged in the same
tumor-bearing animals. Twelve animals were also imaged with (18)F-labeled fluoro-
deoxyglucose ((18)F-FDG). In addition, histological examination was performed, and direct measurement of
tumor oxygenation status carried out with the Oxylite probe system. Two size groups were used, relatively well-oxygenated
tumors in the range of 80-180 mg were designated as small, and those >300 mg and highly hypoxic, as large. Based on the data from 11 MCa and six FSaII
tumors, both (124)I-IAZG and (18)F-FMISO images showed high tracer uptake in the large
tumors. In (18)F-FMISO images at 1, 3-4, and 6-8 h post-injection (p.i.), there was considerable whole-body background activity. In contrast, (124)I-IAZG imaging was optimal when performed at 24-48 h p.i., when the whole-body background had dissipated considerably. As a result, the (124)I-IAZG images at 24-48 h p.i. had higher
tumor to whole-body activity contrast than the (18)F-FMISO images at 3-6 h p.i. Region-of-interest analysis was performed as a function of time p.i. and indicated a
tumor uptake of 5-10% (of total-body activity) for
FMISO at 3-6 h p.i., and of ~17% for IAZG at 48 h p.i. This was corroborated by biodistribution data in that the
tumor-to-normal tissue (T/N, normal tissues of blood, heart, lung, liver, spleen, kidney, intestine, and muscle) activity ratios of IAZG at 24 h p.i. was 1.5-2 times higher than those of
FMISO at 3 h p.i., with the exception of stomach. Statistical analysis indicated that these differences in T/N ratios were significant. The small
tumors were visualized in the (18)F-FDG images, but not in the (124)I-IAZG or (18)F-FMISO images. This was perhaps due to the combined effect of a smaller
tumor volume and a lower hypoxic fraction. Oxylite probe measurement indicated a lesser proportion of regions with pO(2)<2.5 mmHg in the small
tumors (e.g., pO(2) was <2.5 mmHg in 28% and 67% of the data in small and large FSaII
tumors, respectively), and the biodistribution data showed lower uptake of the tracers in the small
tumors than in the large
tumors. In the first study of its kind, using serial microPET imaging in conjunction with biodistribution analysis and direct probe measurements of local pO(2) to evaluate tumor hypoxia markers, we have provided data showing the potential of (124)I-IAZG for
hypoxia imaging.