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 (SUV_mean) in approximately half of the treated tumors. The reduction in SUV_mean correlated with a decrease in the fraction of tumor area staining positive for both EF5 and pimonidazole. Compared with untreated controls, tumors with decreasing SUV_mean had significantly fewer perfused microvessels. Conclusion: ¹⁸F-FMISO PET could distinguish between different tumor responses to DMXAA treatment. However, a reduction in ¹⁸F-FMISO SUV_mean after DMXAA treatment was indicative of reduced perfusion and therefore delivery of ¹⁸FFMISO, rather than a reduction in tumor hypoxia.