COMBINATION THERAPY OF ERYTHROPOIETIN, HYDROXYUREA, AND CLOTRIMAZOLE IN A BETA-THALASSEMIC MOUSE - A MODEL FOR HUMAN THERAPY

beta thalassemia (beta that) in DBA/2J mice is a consequence of the sp ontaneous and complete deletion of the beta major globin gene. Homozyg ous beta that mice have clinical and biological features similar to th ose observed in human beta that intermedia. Erythrocytes in human beta that are characterized by a relative cell dehydration and reduced Kcontent. The role of this erythrocyte dehydration in the reduced eryth rocyte survival, which typifies the disease, has not previously been e valuated. We examined for 1 month the effects on the anemia and the er ythrocyte characteristics of beta that mice of daily treatment with ei ther clotrimazole (CLT), an inhibitor of red blood cell (RBC) dehydrat ion via the Gardos channel, or human recombinant erythropoietin (r-HuE PO), or hydroxyurea (HU). The use of either r-HuEPO or HU induced a si gnificant increase in hemoglobin (Hb), hematocrit (Hct), erythrocyte K + and a decrease in percent reticulocytes, suggesting improved erythro cyte survival. CLT alone decreased only mean corpuscular hemoglobin co ncentration (MCHC) and cell density and increased cell K+. Thus, thoug h the Gardos channel plays a major role in cell dehydration of murine beta thal erythrocytes, its activity does not contribute to reduced er ythrocyte survival. Combination therapy with r-HuEPO plus HU produced no incremental benefit beyond those of single drug therapy. However, a ddition of CLT to r-HuEPO, to HU, or to combined r-HuEPO plus HU led t o statistically significant increases in Hb, Hct, and erythrocyte K+ c ompared with any of the regimens without CLT. These results suggest th at CLT not only inhibits erythrocyte dehydration, but also potentiates the erythropoietic and cellular survival responses to r-HuEPO and HU. (C) 1996 by The American Society of Hematology.