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Validation of the Fluorinated 2-Nitroimidazole SR-4554 as a Noninvasive Hypoxia Marker Detected by Magnetic Resonance Spectroscopy¹

Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom [B. M. S., R. G., F. R., P. W.], and Gray Cancer Institute, Northwood HA6 2JR, United Kingdom [R. J. M., D. J. H., G. M. T.]

Purpose: Tumor hypoxia is associated with poor prognosis and a more malignant tumor phenotype. SR-4554, a fluorinated 2-nitroimidazole, is selectively bioreduced and bound in hypoxic cells. We present validation studies of SR-4554 as a noninvasive hypoxia marker detected by fluorine-19 magnetic resonance spectroscopy (¹⁹F MRS) in the P22 carcinosarcoma, a tumor with clinically relevant hypoxia levels.

Experimental Design: Tumor-bearing female severe combined immunodeficient mice received SR-4554 at 180 mg/kg. Pharmacokinetic studies of parent SR-4554 in plasma and tumors were performed using high-performance liquid chromatography-UV. Total SR-4554 (parent SR-4554 and bioreduction products) was monitored in tumor by ¹⁹F MRS using a 4.7 T spectrometer, with continuous acquisition for up to 5 h. A parameter of total SR-4554 retention, the 3-h ¹⁹F retention index (¹⁹FRI) was determined. Tumor pO₂, assessed polarographically, was decreased (5 mg/kg hydralazine or 100 mg/kg combretastatin A-4 phosphate) or increased [1 l/min carbogen (5% CO₂, 95% O₂) plus 500 mg/kg nicotinamide], and the corresponding ¹⁹FRI was measured.

Results: Comparative HPLC-UV- and MRS-derived assessments of parent and total SR-4554, respectively, indicated that concentrations of total SR-4554 consistently exceeded parent SR-4554, the differential increasing with time. This indicates formation and retention of SR-4554 bioreduction products in tumor, confirming the presence of hypoxia. The ¹⁹FRI was higher in hydralazine- and combretastatin-treated animals compared with unmodulated animals (P = 0.004 and 0.15, respectively) and animals receiving carbogen and nicotinamide (P = 0.0001 and 0.005, respectively). Significant correlations were demonstrated between mean ¹⁹FRI and polarographic pO₂ parameters (P < 0.002).

Conclusions: Retention of hypoxia-related SR-4554 bioreduction products can be detected in the clinically relevant P22 tumor by ¹⁹F MRS, and the ¹⁹FRI correlates with polarographically measured pO₂. These findings support the use of SR 4554 as a noninvasive hypoxia marker.

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