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Tumor-dependent Kinetics of Partial Pressure of Oxygen Fluctuations during Air and Oxygen Breathing

Departments of ¹ Radiation Oncology and ² Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; ³ Department of Anatomy/Cell Biology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; and ⁴ Department of Physiology, Arizona Health Sciences Center University of Arizona, Tucson, Arizona

The primary purpose of this study was to examine the kinetics of partial pressure of oxygen (pO₂) fluctuations in fibrosarcoma (FSA) and 9L tumors under air and O₂ breathing conditions. The overall hypothesis was that key factors relating to oxygen tension fluctuations would vary between the two tumor types and as a function of the oxygen content of the breathing gas. To assist in the interpretation of the temporal data, spatial pO₂ distributions were measured in 10 FSA and 8 9L tumors transplanted into the subcutis of the hind leg of Nembutal-anesthetized (50 mg/kg) Fischer 344 rats. Recessed-tip oxygen microelectrodes were inserted into the tumor, and linear pO₂ measurements were recorded in 50-µm steps along a 3-mm path, and blood pressure was simultaneously measured via femoral arterial access. Additionally, pO₂ was measured at a single location for 90 to 120 minutes in FSA (n = 11) or 9L tumors (n = 12). Rats were switched from air to 100% O₂ breathing after 45 minutes. Temporal pO₂ records were evaluated for their potential radiobiological significance by assessing the number of times they crossed a 10-mm-Hg threshold. In addition, the data were subjected to Fourier analysis for air and O₂ breathing.

FSA and 9L tumors had spatial median pO₂ measurements of 4 and 1 mm Hg, respectively. 9L had more low pO₂ measurements 2.5 mm Hg than did FSA, whereas between 2.5 and 10 mm Hg this pattern was reversed. Pimonidazole staining patterns in FSA and 9L tumors supported these results. Temporal pO₂ instability was observed in all experiments during air and O₂ breathing. Threshold analyses indicated that the 10 mm Hg threshold was crossed 2 to 5 times per hour, independent of tumor type. However, the magnitude of 9L pO₂ fluctuations was approximately eight times greater than FSA fluctuations, as assessed with Fourier transform analysis (Wilcoxon, P < 0.005). O₂ breathing significantly increased median pO₂ in FSA from 3 to 8 mm Hg (P < 0.005) and caused a significant increase in frequency and magnitude of pO₂ fluctuations. One hundred percent O₂ breathing had no effect on 9L tumor pO₂, and it decreased the magnitude of pO₂ fluctuations with borderline significance.

These results show that these two tumors differ significantly with respect to spatial and temporal oxygenation conditions under air and O₂ breathing. Fluctuations of pO₂ of the type reported herein are predicted to significantly affect radiotherapy response and could be a source for genetic instability, increased angiogenesis, and metastases.

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