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Effect of Longitudinal Oxygen Gradients on Effectiveness of Manipulation of Tumor Oxygenation^{1 ,2}

Departments of Radiation Oncology [K. E., R. D. B., J. L., D. M. B., M. W. D.] and Biostatistics and Bioinformatics [D. Y.] Duke University Medical Center. Durham, North Carolina 27710; Departments of Biochemistry and Biophysics [D. W.] and Radiation Oncology [J. E. B.], University of Pennsylvania Philadelphia, Pennsylvania; and Department of Physiology University of Arizona, Tucson, Arizona [T. W. S.]

The purpose of this study was to test the hypothesis that longitudinal O₂ gradients in tumor affect response to manipulation of oxygenation. Previously we showed that pO₂ is higher on the fascial than the tumor surface of the R3230Ac rat mammary carcinoma when growing in a dorsal skin-fold window chamber, reflecting a longitudinal oxygen gradient. Magnetic resonance angiography verified prior results: the fascial surface has arterioles and higher vascular density than tumor; and the tumor surface has no arterioles. Phosphorescence lifetime imaging was used to measure each surface hypoxic percentage (HP; percentage of pixels < 10 mm Hg) before and after administration of mannitol or glucose (1 g/kg, i.v.) followed by O₂ breathing. The fascial surface had a smaller HP (median = 2.72%) than tumor (median = 27.94%; P = 0.0002) at baseline. HP on the fascial surface was positively correlated with HP on the tumor surface (P = 0.0067). HP decreased on the fascial surface after either sugar + O₂ (mannitol P = 0.03; glucose P = 0.06; combined P = 0.002), but HP did not change on the tumor surface. Therefore, the tumor surface is refractory to improvement in pO₂ with this method. Additional refinements may be needed to improve pO₂ of analogous regions in larger tumors; mechanism-driven suggestions are provided.

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