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, and 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, whereas 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 work was to evaluate the toxic effects of the antiviral agent, 3'-azido-3'-deoxythymidine (AZT), the antidiabetic drug, chlorpropamide (CLP), and the heme-analogous compound, protophorphirin IX zinc (II) (ZnPP), on the proliferation of erythroblastic progenitors by using human umbilical-cord blood cells and murine progenitors from long-term bone marrow cultures. All these agents may interfere with the hemopoietic process, causing myelotoxicity as an adverse effect via different mechanisms. Our results showed selective toxicity of the three drugs on the erythroid progenitors (IC(50): AZT 0.35 +/- 0.13 microM, ZnPP 23.34 +/- 1.16 microM, CLP 1.07 +/- 0.27 mM), with respect to the myeloid progenitors (IC(50): AZT 0.8 microM, ZnPP 103.9 +/- 3.9 microM and CLP > 2800 microM). The IC(50) values were well correlated with peak plasma levels reached in vivo by the drugs. There was a marked similarity between the drug sensitivities of the human and murine progenitors but differences in toxicity exerted by the drugs on the basis of the time of exposure. Drug treatment of long-term cultures, followed by the clonogenic assay of progenitors collected from them in the absence of the drugs, generally resulted in a lower hematotoxicity.
Gribaldo
L
L
European Centre for the Validation of Alternative Methods (ECVAM), Institute for Health and Consumer Protection, European Commission Joint Research Centre, 21020 Ispra (VA) Italy. laura.gribaldo@jrc.it
Malerba
I
I
Collotta
A
A
Casati
S
S
Pessina
A
A
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D002478:Cells, Cultured; D002747:Chlorpropamide / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011524:Protoporphyrins / Q000633:toxicity*; D014470:Umbilical Cord / Q000166:cytology; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D007004:Hypoglycemic Agents; D011524:Protoporphyrins; D015215:Zidovudine; C028025:protoporphyrin IX; D002747:Chlorpropamide