Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression.
Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50 microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet < 20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.
MacVittie
T J
TJ
Greenebaum Cancer Center, University of Maryland, Baltimore 21201, USA.
Farese
A M
AM
Smith
W G
WG
Baum
C M
CM
Burton
E
E
McKearn
J P
JP
D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001803:Blood Transfusion; D001855:Bone Marrow Diseases / Q000209:etiology*; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D004307:Dose-Response Relationship, Radiation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007377:Interleukin-3; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000188:drug therapy / Q000209:etiology; D015202:Protein Engineering; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000819:agonists*; D016185:Receptors, Interleukin-3 / Q000819:agonists*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000188:drug therapy / Q000209:etiology; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor