INHIBITORY EFFECTS OF ZIDOVUDINE IN ERYTHROID PROGENITOR CELLS - REVERSAL WITH A COMBINATION OF ERYTHROPOIETIN AND INTERLEUKIN-3

To investigate the mechanisms that may be involved in zidovudine (AZT) -induced hematopoietic toxicity, spleen cells isolated from phenylhydr azine-treated anemic mice or murine bone marrow erythroid progenitor c ells were treated with AZT (1-10 mu M) for 24 hr. A concentration-depe ndent inhibition of the binding of I-125-labeled erythropoietin (Epo) was observed, suggesting downregulation of Epo receptors. To determine if this effect is due to modulation of the levels of Epo receptor mRN A and to assess the effect of AZT on the expression of protooncogenes, mRNA levels were monitored by the slot blot hybridization technique. AZT caused a concentration-dependent inhibition in the levels of the m RNA of Epo receptors and c-fos, whereas the level of c-myc mRNA was un affected. AZT also inhibited protein kinase C (PKC) activity in a conc entration- and time-dependent manner, causing 50% inhibition at 10 mu M within 3 hr. Simultaneous addition of Epo or interleukin-3 (IL-3) pa rtially reversed the inhibitory effects of AZT on the levels of the mR NAs and on PKC activity; however, a combination of Epo and IL-3 was si gnificantly more effective. These studies demonstrate that (i) AZT-ind uced down-regulation of Epo receptors and c-fos expression coupled wit h inhibition of Epo receptor-mediated signal transduction through PKC are significant contributory factors to AZT-induced erythroid toxicity , and (ii) these inhibitory effects can be overcome by treatment with a combination of Epo and IL-3.