ROOT EFFECT HEMOGLOBINS IN CANCER THERAPY

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DESCRIPTION: The purpose of this project is to investigate the potential usefulness of Root effect hemoglobins to improve tumor oxygenation for cancer therapy. Root effect hemoglobins are found in some fish. The Root effect is essentially an exaggerated Bohr effect wherein oxygen affinity is greatly decreased at acid pH. Root effect hemoglobins serve as pressure transducers. Under appropriate circumstances it is possible to load hemoglobin at ambient oxygen pressure, i.e. a human or mammal breathing ambient air, and to deliver oxygen under vastly increased, even hyperbaric, pressure in acidic tissues. Hemoglobin Ill of the American rainbow trout S. gairdneri will be used for this work. At pH 7.4 it demonstrates an oxygen-hemoglobin dissociation curve similar to that of most mammalian hemoglobins. Depending upon the exact experimental conditions, the value of P(50), the partial pressure at which hemoglobin is one-half saturated, at pH circa 6.8 can be as high as 1,000 torr. Two well established rodent tumor systems, the EMT6 mouse mammary carcinoma in BALB/C Rw mice and the BA1112 rhabdomyosarcoma in WAG/Rij rats, which have been shown to contain hypoxic cells resistant to the effects of ionizing radiation, will be used for this study. Trout III hemoglobin will be administered to tumor bearing animals either as stroma-free hemoglobin or as hemoglobin repackaged in liposomes or intact red blood cells. Its effect on tumor hypoxia and radiobiological response will be investigated using oxygen microelectrode measurements and the classic methods for determining "radiobiological hypoxic fraction" including the in vivo-in vitro paired radiation clonogenic cell survival method, tumor regrowth delay, and long-term local tumor control. Preliminary experiments including a direct comparison of the effects of red blood encapsulated Root effect and non-Root effect hemoglobin on tumor oxygenation using the paired radiation cell survival method with the BA1112 rhabdomyosarcoma have demonstrated the potential of this approach. Radiation response will be determined for single radiation treatments and for fractionated courses of radiation therapy. Parallel studies will investigate the effects of the Root effect hemoglobin on the radiation reactions of selected normal tissues including skin, bone regrowth, and the hematopoietic system.