title: Tumor-dependent kinetics of partial pressure of oxygen fluctuations during air and oxygen breathing.
abstract: 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-microm 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 < or =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.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: L Isabel
authors.initials: LI
authors.lastname: Cárdenas-Navia
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Rod D
authors.initials: RD
authors.lastname: Braun
authors.forename: David M
authors.initials: DM
authors.lastname: Brizel
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Secomb
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000388:Air; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism*; D005583:Fourier Analysis; D005910:Glioma / Q000098:blood supply / Q000378:metabolism*; D007150:Immunohistochemistry; D009593:Nitroimidazoles / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D010313:Partial Pressure; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D009593:Nitroimidazoles; C033815:pimonidazole; D010100:Oxygen