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

Lookup NU author(s): Dr Ross Maxwell

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Abstract

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 combretastatintreated 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.


Publication metadata

Author(s): Seddon BM, Maxwell RJ , Grimshaw R, Raynaud F, Tozer GM, Workman P, Honess DJ

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2002

Volume: 8

Issue: 7

Pages: 2323-2335

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://clincancerres.aacrjournals.org/cgi/reprint/8/7/2323

Notes: RJM proposed and supervised animal magnetic resonance study based on earlier work with PW on another potential hypoxia marker. Study supports clinical research with this marker using magnetic resonance techniques.


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