18F-Fluromisonidazole PET Imaging as a Biomarker for the Response to 5,6-Dimethylxanthenone-4-Acetic Acid in Colorectal Xenograft Tumors

The aim of this study was to evaluate 18F-fluromisonidazole (18F-FMISO) PET for monitoring the tumor response to the antivascular compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA; vadimezan). Methods: 18F-FMISO PET was performed 3 h before and 24 h after treatment with DMXAA (20 mg/kg) in mice bearing HT29 xenograft tumors. Pimonidazole was coadministered with the first 18F-FMISO injection, and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) was coadministered with the second one. Hoechst 33342 was administered 5 min before sacrifice. Digital autoradiograms of tumor sections were acquired; this acquisition was followed by immunofluorescence microscopic visualization of pimonidazole, EF5, the Hoechst 33342, CD31, and α-smooth muscle actin. Results: DMXAA treatment resulted in a marked reduction in the 18F-FMISO mean standardized uptake value (SUVmean) in approximately half of the treated tumors. The reduction in SUVmean correlated with a decrease in the fraction of tumor area staining positive for both EF5 and pimonidazole. Compared with untreated controls, tumors with decreasing SUVmean had significantly fewer perfused microvessels. Conclusion: 18F-FMISO PET could distinguish between different tumor responses to DMXAA treatment. However, a reduction in 18F-FMISO SUVmean after DMXAA treatment was indicative of reduced perfusion and therefore delivery of 18F-FMISO, rather than a reduction in tumor hypoxia.

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