AMELIORATION OF AZIDOTHYMIDINE-INDUCED ERYTHROID TOXICITY BY HEMIN AND STEM-CELL FACTOR IN IMMUNE-SUPPRESSED MICE

Recombinant cytokines such as stem cell factor (SCF) are currently bei ng tested for the ability to ameliorate 3'azido-3'deoxythymidine (AZT) -induced anemia in AIDS patients. Recently, we showed that SCF greatly increased burst-forming units-erythroid (BFU-E) but failed to increas e hematocrits of AZT-treated immune-deficient (MAIDS) mice. We reasone d that hemin, previously shown to both enhance BFU-E proliferation and accelerate erythroid maturation, might bring about differentiation of this large SCF-induced pool of BFU-E and further protect BFU-E from A ZT's toxic effect. We therefore studied, in vitro, the effect of combi nations of hemin and SCF on growth of BFU-E from MAIDS mice. Hemin, at concentrations of 10 to 100 mu M, ameliorated the growth-inhibitory e ffect of AZT. 50 mu M hemin increased the ED(50) of AZT from 1x10(-7)M to 1.7x10(-6)M. SCF also ameliorated AZT-induced toxicity, but to a l esser extent. SCF and hemin increased the number of BFU-E colonies obs erved in the presence of AZT in an additive fashion. The resistance of BFU-E to AZT's cytotoxic effect was greater in cultures receiving hem in and SCF together than in cultures receiving SCF or hemin alone. Zin c and tin protoporphyrins (Zn and Sn PP) increased the numbers of BFU- E observed. However, neither zinc nor tin protoporphyrins increased th e ED(50) of AZT. Combinations of SCF and hemin may prove useful in ame liorating AZT toxicity in both immune-suppressed mice and human immuno deficiency virus (HIV-infected patients.