Effect of 6-hydroxydopamine on murine hematopoietic stem cells: enhanced cytotoxicity on megakaryocyte colony forming units.
We examined the effect of catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on murine committed megakaryocyte progenitor cells, the megakaryocyte-colony forming unit (CFU-Meg). More mature cells of the megakaryocyte series have the capacity for active uptake of catecholamines, and we speculated that the CFU-Meg would also take up 6-OHDA and be selectively killed. CFU-Meg were much more sensitive to the effects of this agent than were granulocyte-macrophage colony forming units (CFU-GM) or spleen-colony forming units. Co-incubation with catalase, which would destroy hydrogen peroxide generated extracellularly by the autoxidation of 6-OHDA, ablated 6-OHDA toxicity towards CFU-GM, but also significantly reduced the effect on CFU-Meg. Mazindol, a selective dopamine uptake inhibitor did not alter 6-OHDA effect on either CFU-Meg or CFU-GM. Finally, CFU-Meg were no more sensitive to incubation with hydrogen peroxide than were CFU-GM. These data suggest that CFU-Meg, unlike their more mature progeny, do not actively concentrate 6-OHDA, and the excess toxicity of this agent towards CFU-Meg is probably due to increased sensitivity to autoxidation products of 6-OHDA, other than hydrogen peroxide, generated extracellularly.
Gordon
B G
BG
Section of Pediatric Hematology/Oncology and Bone Marrow Transplantation, University of Nebraska Medical Center, Omaha.
DeBoer
J M
JM
Wooldridge
L D
LD
Sharp
J G
JG
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006892:Hydroxydopamines / Q000378:metabolism / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology; D008454:Mazindol / Q000494:pharmacology; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D016627:Oxidopamine; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured
D006892:Hydroxydopamines; D016627:Oxidopamine; D008454:Mazindol