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Objectives: The objectives of the study were to test the hypothesis that hyperbaric levels of oxygen enhance the sensitivity of a sarcoma cell line to doxorubicin (Adriamycin) both in vitro and in vivo in a rat model of pulmonary metastases and to test the feasibility of arterialization of mixed venous blood by direct injection of aqueous oxygen into the pulmonary artery in a rat model., Methods: Rat sarcoma (MCA-2) cells were incubated in the presence of increasing concentrations of doxorubicin (0.1-2.0 micromol/L). A dose-dependent toxicity relationship at 12 hours of treatment was examined with and without pretreatment with hyperbaric oxygen (3.7 atm absolute for 1.5-3.5 hours). In vivo, Sprague-Dawley rats (n = 24) were injected intravenously with 10(6) MCA-2 cells, and the lung tumors were allowed to mature for 14 days. At that time the animals were divided into four groups: control (no treatment), doxorubicin at 2 mg/kg, hyperbaric oxygen (oxygen at 2 atm absolute for 30 minutes), and hyperbaric oxygen plus doxorubicin. Seven days after treatment, the numbers of lung nodules were counted and the lung weights were determined. In additional rats (n = 7), aqueous oxygen (1 mL oxygen/g saline solution) was infused into the pulmonary artery to determine whether arterialization of mixed venous blood was comparable to pulmonary artery oxygenation with a hyperbaric chamber (n = 7)., Results: Hyperbaric oxygen plus doxorubicin produced significantly greater cytolysis of MCA-2 cells (P <.01) than did doxorubicin alone. Hyperbaric oxygen plus doxorubicin also significantly decreased the number of lung metastases and the lung weight relative to doxorubicin alone (P <.01 and P <.01, respectively). The feasibility of arterialization of mixed venous blood (>100 mm Hg) with aqueous oxygen infusion was demonstrated., Conclusions: Hyperbaric oxygen enhanced the chemotherapeutic effect of doxorubicin both in cell culture and in the rat model. Aqueous oxygen infusion can be used to oxygenate mixed venous blood at levels similar to those obtained with the use of a hyperbaric chamber.