Inhibition of CFU-E/BFU-E by 3 '-azido-3 '-deoxythymidine, chlorpropamide,and protoporphirin IX zinc (II): A comparison between direct exposure of progenitor cells and long-term exposure of bone marrow cultures

Erythropoiesis occurs in two stages: proliferation amplifies cell number, a nd differentiation stimulates the acquisition of the functional properties of red blood cells. The erythroid colony-forming unit (CFU-E) amplifies the differentiation process in response to erythropoietic stress in vitro, whe reas the burst-forming unit (BFU-E), which is not particularly sensitive to erythropoietin stimulation, gives rise to the CFU-E and, when stimulated, produces morphologically-identifiable erythroid colonies. The aim of this w ork was to evaluate the toxic effects of the antiviral agent, 3'-azido-3'-d eoxythymidine (AZT), the antidiabetic drug, chlorpropamide (CLP), and the h eme-analogous compound, protophorphirin IX zinc (II) (ZnPP), on the prolife ration of erythroblastic progenitors by using human umbilical-cord blood ce lls and murine progenitors from long-term bone marrow cultures. All these a gents may interfere with the hemopoietic process, causing myelotoxicity as an adverse effect via different mechanisms. Our results showed selective to xicity of the three drugs on the erythroid progenitors (IC50: AZT 0.35 +/- 0.13 muM, ZnPP 23.34 +/- 1.16 muM, CLP 1.07 +/- 0.27 mM), with respect to t he myeloid progenitors (IC50: AZT 0.8 muM, ZnPP 103.9 +/- 3.9 muM and CLP > 2800 muM). The IC50 values were well correlated with peak plasma levels re ached in vivo by the drugs. There was a marked similarity between the drug sensitivities of the human and murine progenitors but differences in toxici ty exerted by the drugs on the basis of the time of exposure. Drug treatmen t of long-term cultures, followed by the clonogenic assay of progenitors co llected from them in the absence of the drugs, generally resulted in a lowe r hematotoxicity.