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The 9L gliosarcoma growing subcutaneously in the hind leg of the Fisher 344 rat contains major areas of severe (<5 mmHg) hypoxia, making up about 49% of the tumor. Intravenous administration of an ultrapurified polymerized bovine hemoglobin solution (8 ml/kg) along with normal air breathing reduces the percentage of severe hypoxia to about 24% and increases oxygenation throughout the tumor. Coadministration of the hemoglobin solution increased the tumor growth delay of subcutaneously implanted 9L tumors treated with carmustine (BCNU), cyclophosphamide, or ifosfamide but did not significantly change the tumor growth delay produced by cisplatin (CDDP). Coadministration of the hemoglobin solution with each of the four antitumor alkylating agents resulted in a near doubling of the percentage of increase in life span in animals bearing intracranial tumors treated with the combination as compared with animals treated with the drugs alone. Increases in serum blood urea nitrogen (BUN) and creatinine levels in treated animals returned to normal by 11 days posttreatment. Major changes in liver enzymes occurred with the combination of cyclophosphamide and the hemoglobin solution at 4 days posttreatment; however, these values returned to the levels in the untreated control animals within 1 week thereafter. These results indicate that further exploration of the use of hemoglobin solutions in cancer therapy is warranted.