Co-administration of Flt-3 ligand counteracts the actions of thrombopoietin in myelosuppressed rhesus monkeys.
This placebo-controlled study evaluated the efficacy of Flt-3 ligand (FL) combined with TPO in myelosuppressed rhesus monkeys. The monkeys were subjected to 5 Gy total body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either 5 microg/kg of rhesus TPO i.v. on d 1 (n = 4) and 100 microg/kg/d s.c. human FL (n = 4) or FL alone (n = 4) for 14 consecutive days and were compared with results from a concomitant study involving the administration of TPO alone (n = 4) or placebo (carrier; n = 4). The TPO/FL combination was considerably less effective than TPO alone, with a more profound nadir and a slower recovery to thrombocyte counts > 100 x 109/l, approaching recovery patterns of placebo controls. Leucocyte regeneration was similar in all animals. Monkeys treated with FL alone displayed a regeneration of reticulocytes and thrombocytes in the lower range of those of the placebo controls. Recovery of bone marrow (BM) cellularity was slightly accelerated in the TPO/FL-treated monkeys, but was not reflected by an increase in progenitor cells, in contrast to TPO alone. Monkeys treated with FL alone showed a BM reconstitution similar to placebo-treated controls. FL by itself was not effective as a therapeutic agent in this model for myelosuppression. As FL also suppressed BM CD34+ cell reconstitution, we concluded that FL competed with TPO at the level of immature cell differentiation.
Hartong
Simone C C
SC
Institute of Haematology, Erasmus University Rotterdam, Rotterdam, the Netherlands.
Neelis
Karen J
KJ
Wagemaker
Gerard
G
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002452:Cell Count; D004359:Drug Therapy, Combination; D004906:Erythrocyte Count; D005434:Flow Cytometry; D008253:Macaca mulatta; D008297:Male; D008565:Membrane Proteins / Q000627:therapeutic use*; D023421:Models, Animal; D010976:Platelet Count; D011994:Recombinant Proteins / Q000627:therapeutic use; D013234:Stem Cells / Q000473:pathology; D013921:Thrombocytopenia / Q000188:drug therapy* / Q000473:pathology; D013926:Thrombopoietin / Q000627:therapeutic use*; D014916:Whole-Body Irradiation
D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D013926:Thrombopoietin