Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression
| Autor: | T J, MacVittie, A M, Farese, W G, Smith, C M, Baum, E, Burton, J P, McKearn |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Neutropenia Recombinant Fusion Proteins Drug Evaluation Preclinical Dose-Response Relationship Radiation Hematopoietic Cell Growth Factors Protein Engineering Macaca mulatta Thrombocytopenia Receptors Interleukin-3 Recombinant Proteins Blood Cell Count Hematopoiesis Colony-Forming Units Assay Radiation Injuries Experimental Drug Design Granulocyte Colony-Stimulating Factor Receptors Granulocyte Colony-Stimulating Factor Animals Blood Transfusion Cell Lineage Interleukin-3 Bone Marrow Diseases Whole-Body Irradiation |
| Zdroj: | Blood. 95(3) |
| ISSN: | 0006-4971 |
| Popis: | 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 (platelet20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to500/microL) and platelets (PLT20,000/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. |
| Databáze: | OpenAIRE |
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