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Marking Hypoxia in Rat Prostate Carcinomas with ß-D-[¹²⁵I]Azomycin Galactopyranoside and [^99mTc]HL-91: Correlation with Microelectrode Measurements

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

The purpose of this study was to determine, with a rodent tumor model, if microelectrode measurements of unmodulated tumor oxygenation predict for the avidity of hypoxic markers to tumor tissue. Methods: The rapidly growing, anaplastic variant of the Dunning rat prostate carcinoma cell line (R3327-AT) was implanted subcutaneously on the upper backs of Fischer X Copenhagen rats. Approximately 100 measurements of PO₂ were obtained from tumors of 5–10 g in animals that were restrained and then subjected to different anesthetic procedures. Values of median PO₂ (in mm Hg) and percentage of measurements <5 mm Hg obtained from individual tumors were used to define tumor oxygenation status. The radiodiagnostic hypoxic markers ß-D-iodinated azomycin galactopyranoside (IAZGP) and [^99mTc]HL-91 were simultaneously administered to 26 animals whose tumor oxygen levels had been measured. Six hours after marker administration, the animals were killed; tumor, blood, and muscle tissues were sampled; and percentage injected dose per gram (%ID/g*), tumor/blood ratio (T/B), and tumor/muscle ratio (T/M) parameters were determined. Parameters of marker avidity to individual tumors were linearly correlated with microelectrode measurements of tumor oxygenation to determine the significance of inverse associations. Results: The median PO₂ of 41 tumors varied from 2.0 to 20.9 mm Hg, with an average value of 7.5 ± 1.4 mm Hg. Six tumors had unusually high values; that is, >10 mm Hg, and when these were excluded from the analysis, the average median PO₂ of the remaining 35 was 4.3 ± 0.7 mm Hg. When electrode measurements of tumor oxygenation were obtained under conditions of halothane anesthesia with the animals breathing O₂, carbogen, or air, median PO₂ values increased significantly (P = 0.001). When animals were deeply anesthetized by intraperitoneal injection of ketamine-xylazine, median PO₂ values were not significantly different (P = 0.13) from those obtained while the animals were restrained and breathing air. There was no inverse correlation of significance between the electrode measurements of median PO₂ and the avidity of ß-D-IAZGP nor [^99mTc]HL-91 in this tumor model. The range of median PO₂ values in these tumors was at least 3 mm Hg, and the range of hypoxic marker avidity was less than twofold. Conclusion: These data demonstrate that microelectrode measurements of rat tumor oxygenation did not correlate with the avidity of the two hypoxic markers, at least in this tumor model. The larger dynamic range of tumor oxygen measurements obtained with microelectrodes might be biased to low values by their necrotic fractions, the zones within solid tumors that contain dead cells and debris that will not be labeled by bioreducible hypoxic markers. Hypoxic marker avidity to individual tumors will have to be validated by other assays that can predict for their radiosensitivity.

Key Words: halothane • anesthesia • Eppendorf PO₂ microelectrode • HL-91 • ß-D-IAZGP • hypoxic markers • tumor oxygenation

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