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 being 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 increase hematocrits of AZT-treated immune-deficient (MAIDS) mice. We reasoned 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 AZT's toxic effect. We therefore studied, in vitro, the effect of combinations of hemin and SCF on growth of BFU-E from MAIDS mice. Hemin, at concentrations of 10 to 100 microM, ameliorated the growth-inhibitory effect of AZT. 50 microM hemin increased the ED50 of AZT from 1 x 10(-7) M to 1.7 x 10(-6) M. SCF also ameliorated AZT-induced toxicity, but to a lesser extent. SCF and hemin increased the number of BFU-E colonies observed in the presence of AZT in an additive fashion. The resistance of BFU-E to AZT's cytotoxic effect was greater in cultures receiving hemin and SCF together than in cultures receiving SCF or hemin alone. Zinc and tin protoporphyrins (Zn and Sn PP) increased the numbers of BFU-E observed. However, neither zinc nor tin protoporphyrins increased the ED50 of AZT. Combinations of SCF and hemin may prove useful in ameliorating AZT toxicity in both immune-suppressed mice and human immunodeficiency virus (HIV)-infected patients.
Hamburger
A W
AW
University of Maryland Cancer Center/Department of Pathology, Baltimore 21201.
Chen
R B
RB
D000818:Animals; D004920:Erythropoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006418:Heme / Q000494:pharmacology; D006427:Hemin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy; D019089:Stem Cell Factor; D015215:Zidovudine / Q000037:antagonists & inhibitors*
D016298:Hematopoietic Cell Growth Factors; D019089:Stem Cell Factor; D006418:Heme; D015215:Zidovudine; D006427:Hemin