Alterations in oxygen transport following WR-2721

The toxicity of radiation and alkylating agent chemotherapy is in part related to free radical formation in DNA and associated proteins, which is enhanced by oxygen and other electron affinic compounds. During the Phase I clinical trials of WR-2721 and alkylating agent chemotherapy, venous blood samples were obtained prior to and immediately following the WR-2721 infusion. We have observed a marked increase in the oxygen saturation of venous blood following WR-2721 (430-910 mg/m2 at a rate of 15 mg/m2/minute). The mean venous PO2 (PvO2) rose from a baseline of 34.0 +/- 13.54 torr to a mean value of 54.60 +/- 12.47 torr (p less than 0.001). The percent venous oxygen saturation increased from 54.52 +/- 21.38% to 82.73 +/- 7.66%. The highest values generally occurred within the first 2 hours after the completion of the WR-2721 infusion. No significant differences were found between the pre and post WR-2721 values for either the venous pH, CO2, or bicarbonate levels. Despite increased PvO2, the patients' heart rates, blood pressures, or respiratory rates did not change pre and post WR-2721. No apparent differences were noted in the effects of WR-2721 or PvO2 when given at doses of 740 or 910 mg/m2. However, when WR-2721 (418-1100 mg/m2) was administered over 15 minutes, the PvO2 increased in only 8/13 courses. We postulated that the marked increase in venous blood oxygen concentration was secondary to one of the following mechanisms: 1) Increased affinity of hemoglobin for oxygen, 2) microcirculatory shunting, or 3) decreased tissue requirements for oxygen. In 12 patients oxygen-hemoglobin dissociation curves and intracellular red cell pH's were obtained before and after 740-910 mg/m2 of WR-2721. Despite the significant increase in oxygenation of venous blood after WR-2721, there were no changes in either oxygen-hemoglobin dissociation or intracellular red cell pH to account for this increase. The oxygen consumption of peripheral blood granulocytes was measured prior to and following 15 courses of WR-2721. A marked decrease in granulocyte oxygen consumption was observed in 6/8 patients who had a significant increase in PvO2 and only 1/7 patients who had either a decrease or no change in PvO2 after WR-2721. Our preliminary investigations suggest that the increased venous blood oxygen content may be secondary to a reduction in normal tissue oxygen consumption. WR-2721 may afford protection by both decreasing oxygen consumption and delivery to normal tissues and increasing intracellular sulfhydryls.