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

• Published in: Clinical cancer research Vol. 8; no. 7; pp. 2323 - 2335
• Main Authors: SEDDON, Beatrice M, MAXWELL, Ross J, HONESS, Davina J, GRIMSHAW, Rachel, RAYNAUD, Florence, TOZER, Gillian M, WORKMAN, Paul
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2002
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Biomarkers, Tumor - pharmacokinetics; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; Experimental tumors, general aspects; Female; Fluorine Radioisotopes; Hypoxia - diagnosis; Hypoxia - metabolism; Magnetic Resonance Spectroscopy - methods; Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms, Experimental - diagnosis; Neoplasms, Experimental - metabolism; Nitroimidazoles - pharmacokinetics; Oxygen - metabolism; Polarography; Rats; Tissue Distribution; Tumors; Imidazole derivatives; Magnetic resonance; Tumoral tissue; Rodentia; Biological marker; Fluorine compound; NMR spectrometry; Malignant tumor; Diagnostic agent; Vertebrata; Mammalia; Investigation method; Mouse; Animal; Hypoxia; Medical imagery
• ISSN: 1078-0432; 1557-3265

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 ( 19 F 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 19 F 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 19 F retention index ( 19 FRI) was determined. Tumor pO 2 , assessed polarographically, was decreased (5 mg/kg hydralazine or 100 mg/kg combretastatin A-4 phosphate) or increased [1 l/min carbogen (5% CO 2 , 95% O 2 ) plus 500 mg/kg nicotinamide], and the corresponding 19 FRI 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 19 FRI 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 19 FRI and polarographic pO 2 parameters ( P < 0.002). Conclusions: Retention of hypoxia-related SR-4554 bioreduction products can be detected in the clinically relevant P22 tumor by 19 F MRS, and the 19 FRI correlates with polarographically measured pO 2 . These findings support the use of SR 4554 as a noninvasive hypoxia marker.