In vivo and in vitro effects of 3-hydroxypyridin-4-one chelators on murine hemopoiesis.
The effects of 3-hydroxypyridin-4-one (HPO) iron chelators and desferrioxamine (DFO) on murine hemopoiesis in vivo and in vitro have been compared in order to investigate the mechanism by which leucopenia in mice and granulocytopenia in man occurs with 1,2-,dimethyl-HPO (CP20). Administration of 60 doses of 200 mg/kg CP20 to Balb/c mice resulted in significant anemia, lymphopenia and granulocytopenia accompanied by bone marrow hypocellularity. DFO and CP94 (1,2,diethyl-HPO) at the same dose also caused lymphopenia but marrow cellularity was unaffected. When marrow from untreated mice was incubated with HPOs and DFO, erythroid burst-forming cells (BFU-E) and granulocyte/macrophage colony forming units (CFU-G+Mac), colony growth was inhibited in a dose-dependent manner at micromolar concentrations. The addition of iron to saturate the chelators abrogated the effects of DFO, but not those of the HPOs. With the HPO-iron complexes, addition of sufficient iron to saturate the transferrin in the medium reversed the inhibitory effects of the relatively hydrophilic CP20-iron complex but not those of the more lipophilic CP94-iron complex. Addition of further iron-saturated transferrin also corrected inhibition by the CP94-iron complex. These results show that HPO-iron complexes potentially have antiproliferative effects unlike DFO-iron complex (FO). The difference in the relative effects of CP20 to CP94 on hemopoiesis in vivo and in vitro suggests that additional factors to those inhibiting hemopoiesis in marrow cultures may operate with the long-term administration of iron chelators in vivo.
Hoyes
K P
KP
Department of Clinical Haematology, University College and Middlesex School of Medicine, London, UK.
Jones
H M
HM
Abeysinghe
R D
RD
Hider
R C
RC
Porter
J B
JB
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004906:Erythrocyte Count; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007958:Leukocyte Count; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011728:Pyridones / Q000494:pharmacology*; D014168:Transferrin / Q000378:metabolism
D007502:Iron Chelating Agents; D011728:Pyridones; D014168:Transferrin; C020366:3-hydroxy-4-pyridone; D007501:Iron; D003676:Deferoxamine