Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy.
OBJECTIVE
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.


METHODS
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.
Seddon
Beatrice M
BM
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Maxwell
Ross J
RJ
Honess
Davina J
DJ
Grimshaw
Rachel
R
Raynaud
Florence
F
Tozer
Gillian M
GM
Workman
Paul
P
D000818:Animals; D014408:Biomarkers, Tumor / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D005260:Female; D005462:Fluorine Radioisotopes; D000860:Hypoxia / Q000175:diagnosis* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D010100:Oxygen / Q000378:metabolism; D011048:Polarography; D051381:Rats; D014018:Tissue Distribution
D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; C095171:SR 4554; D010100:Oxygen