Determining Hypoxic Fraction in a Rat Glioma by Uptake of Radiolabeled Fluoromisonidazole

Abstract

The usefulness of radiolabeled nitroimidazoles for measuring hypoxia will be clarified by defining the relationship between tracer uptake and radiobiologically hypoxic fraction. We determined the radiobiologically hypoxic fraction from radiation response data in 36B10 rat gliomas using the paired cell survival curve technique and compared the values to the radiobiologically hypoxic fraction inferred from mathematical modeling of time-activity data acquired by PET imaging of [(18)F]FMISO uptake. Rats breathed either air or 10% oxygen during imaging, and timed blood samples were taken. The uptake of [(3)H]FMISO by 36B10 cells in vitro provided cellular binding characteristics of this radiopharmaceutical as a function of oxygen concentration. The radiobiologically hypoxic fraction determined for tumors in air-breathing rats using the paired survival curve technique was 6.1% (95% CL = 4.3- 8.6%), which agreed well with that determined by modeling FMISO time-activity data (7. 4%; 95% CL = 2.5-17.3%). These results are consistent with the agreement between the two techniques for measuring radiobiologically hypoxic fraction in Chinese hamster V79 cell spheroids. In contrast, the FMISO-derived radiobiologically hypoxic fraction in rats breathing 10% oxygen was 13.1% (95% CL 7.9-8.3%), much lower than the radiobiologically hypoxic fraction of 43% determined from the radiation response data. This discrepancy may be due to the failure of FMISO to identify hypoxic cells residing at or above an oxygen level of 2-3 mmHg that will still confer substantial protection against radiation. The presence of transiently hypoxic cells in rats breathing reduced oxygen may also be under-reported by nitroimidazole binding, which is strongly dependent on time and concentration.

In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography

“…Carbogen breathing decreased the 60-min tumour retention of [ 18 F]FETA by 36%, in keeping with an 11% decrease of hypoxic pO 2 values measured by OxyLite electrodes. This finding is similar to those reported previously for other 2-nitroimidazoles (Aboagye et al, 1997b(Aboagye et al, , 1998Rasey et al, 2000;Bentzen et al, 2002;Seddon et al, 2002) and demonstrates that [ 18 F]FETA can be used to detect acute changes in pO 2 .…”

Positron emission tomography to assess hypoxia and perfusion in lung cancer

“…Bentzen et al [195] , Rasey et al [196] , Bentzen et al [197] , Troost et al [198] Bentzen et al [125] , Gagel et al [126] , Bruehlmeier et al [199] , Lawrentschuk et al [200] , O'Donoghue et al [72] , Piert et al [166] , Sørensen et al [201] , Gagel et al [202] , Carlin et al [203] , Chang et al [204] , Mortensen et al [127] Hatano et al [205] , Huang et al [206] , Huang et al [207] , Oehler et al [208] , Cho et al [209] , Troost et al [210] , Matsumoto et al [136] , Troost et al [198] , Dubois et al [211] Dubois et al [211] , Cherk et al [212] , Riesterer et al [213] , Lehmann et al [214] , Chen et al [215] , Campanile et al [216] , Cheng et al [217] , Sato et al [218] , Norikane et al [219] Cherk et al [212] , Eschmann et al [77] , Gagel et al [82] , Koh et al [87] , Rasey et al [220] , Vera et al…”

Hypoxia and Glucose Metabolism in Malignant Tumors

“…Hypoxia is widely recognized to be an independent predictor of clinical outcome (3,24), but hypoxia in tumors is not predicted by tumor size, grade, extent of necrosis, or blood hemoglobin status. Thus, determination of tumor hypoxia carries information independent of current clinicopathological parameters and can provide important prognostic information.…”