Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI measurements

Abstract

Purpose : Blood oxygen level dependent (BOLD) contrast in magnetic resonance imaging (MRI) has been widely used for noninvasive evaluation of the effects of tumor-oxygenating agents. However, there have been few tests of the validity of this method. The goal of the present work was to use the T 1 of fluorine-19 in perfluorocarbon (PFC) emulsions as a “gold standard” for comparison with BOLD MRI. Methods and Materials : Rats bearing R3230AC tumors implanted in the hind limb were injected with an emulsion of perfluoro-15-crown-5-ether for 2–3 days before experiments, which ensured that the PFC emulsion concentrated in the tumors. We correlated changes in tumor oxygenation caused by carbogen inhalation measured by 1H BOLD MRI with quantitative 19F measurements. The 19F spin-lattice relaxation rate R 1 (= 1/T 1) was measured to determine initial oxygen tension (pO 2) in each image pixel containing the PFC, and changes in pO 2 during carbogen (95% O 2, 5% CO 2) breathing. In a second carbogen breathing period, changes in water signal linewidth were measured using high spectral and spatial resolution imaging. 19F and 1H measurements were used to classify pixels as responders to carbogen (pixels where oxygen increased significantly) or nonresponders (no significant change in tumor oxygenation). Results : The 19F and 1H measurements agreed in 65% ± 11% of pixels ( n = 14). Agreement was even stronger among pixels where 1H showed increased oxygenation; 19F measurements agreed with 1H measurements in over 79% ± 11% of these pixels. Similarly, there was strong agreement between the two modalities in pixels where 19F reported no change in pO 2; 1H also showed no changes in 76% ± 18% of these pixels. Quantitative correlation of changes T 2∗ (ΔT 2∗) in 1H and changes R 1 (ΔR 1) in 19F was weak during carbogen breathing, and averaged over the whole tumor was ∼0.40 for 14 experiments. However, the spatial patterns of 1H and 19F changes were qualitatively very similar. In hypoxic regions that were identified based on long 19F T 1 (>2.53 s), 19F and 1H MRI agreed that carbogen had relatively weak effects. Conclusions : These results suggest that 1H BOLD MRI reliably identifies increases in tumor pO 2. In hypoxic regions where increases in pO 2 are most desirable, carbogen was ineffective. The data suggest that 19F and 1H MRI can be used individually or in combination to guide the design of improved tumor-oxygenating agents.