Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis.
Preservation of hematopoietic stem and progenitor cell survival is required for recovery from radiation-induced myelosuppression. We recently showed that short-term injection of antiapoptotic cytokine combinations into mice soon after lethal gamma irradiation promoted survival. The present study investigated the hematopoietic response of cynomolgus monkeys to a single dose of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination (4F, each factor given intravenously at 50 microg/kg) administered 2 hours after 5-Gy gamma irradiation. Treated monkeys (n = 4) experienced no thrombocytopenia. Only 1 in 4 displayed a transient period of neutropenia (neutrophil [ANC] count < 0.5 x 10(9)/L), whereas all irradiated controls (n = 4) experienced neutropenia (5-12 days) and thrombocytopenia (platelet [PLT] count < 20 x 10(9)/L, 5-31 days). Treated animals exhibited an impressive 2-wave PLT response that peaked at days 8 and 22 after total body irradiation (TBI). Areas under the curve (AUC) of PLTs, ANCs, white blood cells (WBCs), and red blood cells (RBCs) between days 0 and 90 were significantly higher in treated animals than in controls. Humeral bone marrow-derived clonogenic activity was significantly spared at 24 hours and 4 days after TBI in treated monkeys. No apparent impairment of the hematopoietic status and stem cell pool, in terms of long-term culture-initiating cells (LTC-ICs) and side population (SP) cells, was observed after 15 months. These results strongly suggest that the 4F cytokine combination, as a single dose regimen, could act as an emergency treatment for nuclear accident or terrorism victims.
Drouet
Michel
M
Centre de Recherches du Service de Santé des Armées, Department of Radiobiology-Radiohematology Unit, 24 Avenue des Maquis du Grésivaudan, 38702, La Tronche, Cedex, France.
Mourcin
Frédéric
F
Grenier
Nancy
N
Leroux
Valérie
V
Denis
Josianne
J
Mayol
Jean-François
JF
Thullier
Philippe
P
Lataillade
Jean-Jacques
JJ
Herodin
Francis
F
D000818:Animals; D003114:Colony-Forming Units Assay; D005720:Gamma Rays; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D007377:Interleukin-3 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011832:Radiation Injuries / Q000188:drug therapy; D018788:Radioactive Hazard Release; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D019089:Stem Cell Factor / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013926:Thrombopoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D007377:Interleukin-3; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D013926:Thrombopoietin