Manipulations in the oxygen transport capacity of blood as a means of sensitizing tumors to radiation therapy.
Tumor response to radiation is dependent not only on the quantity of hemoglobin (Hb) available for oxygen (O2) transport but also on the position of the Hb-O2 dissociation curve (Hb affinity). Previous studies have shown that administering agents which shift the Hb-O2 dissociation curve to the right (decrease Hb affinity) sensitize tumors to radiation by reducing the fraction of radiobiologically hypoxic cells. However, there may be toxicity limitations when agents aimed at altering Hb affinity are administered directly to the host. The present studies evaluated the therapeutic benefit of shifting the Hb-O2 dissociation curve in vitro prior to the transfusion of the biochemically modified RBCs into recipient hosts. Mice were given a hemolysis agent (phenylhydrazine hydrochloride, PH) prior to transfusing RBCs with normal or altered Hb affinity. A 100 mg/kg dose of PH reduced the hematocrit to approximately 60% of control 24 hr after treatment. Tumors irradiated at this time demonstrated an increased fraction of hypoxic cells. If the hematocrit was returned to normal by transfusing mice prior to irradiation, a significant but transient reduction in the hypoxic fraction was seen. Tumor response was reduced if RBCs with elevated Hb affinity, obtained by storing the erythrocytes at 4 degrees C, were used. Alternatively, tumor sensitization was noted when animals were transfused with RBCs having decreased Hb affinities. The latter was achieved by incubating the RBCs in the presence of either clofibrate or the precursors of 2,3 diphosphoglycerate (2,3 DPG). These findings further support the notion that the Hb affinity is an important parameter in determining tumor response to radiation and suggest that this factor ought to be considered when RBCs are used to transfuse anemic patients undergoing radiotherapy.