Mast cell growth factor enhances multilineage hematopoietic recovery in vivo following radiation-induced aplasia.
Based on in vitro studies, mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has been implicated as an important hematopoietic regulator, especially in the presence of additional hematopoietic cytokines. Since hematopoietic regeneration follows sublethal radiation-induced hematopoietic injury and is thought to be mediated by endogenously produced cytokines, the ability to accelerate recovery from radiation-induced hematopoietic hypoplasia was used to evaluate in vivo effects of MGF administration. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline or 100, 200, or 400 micrograms/kg/d recombinant murine MGF on days 1 to 17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-S), granulocyte-macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC), and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF accelerated hematopoietic recovery at the 100 and 200 micrograms/kg/d doses. The 100 micrograms/kg/d dose accelerated recovery of only GM-CFC, while the 200 micrograms/kg/d dose accelerated CFU-S, GM-CFC, WBC, and PLT recoveries. In contrast, hematopoietic recovery was delayed in mice receiving the 400 micrograms/kg/d dose. These studies demonstrate the in vivo dose-dependent ability of MGF to accelerate multilineage hematopoietic regeneration following radiation-induced hematopoietic hypoplasia. They also document detrimental effects of providing "supraoptimal" doses of this growth factor and suggest caution in dose-escalation trials in humans.
Patchen
M L
ML
Department of Experimental Hematology, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603.
Fischer
R
R
Schmauder-Chock
E A
EA
Williams
D E
DE
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006410:Hematopoiesis / Q000502:physiology* / Q000528:radiation effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008815:Mice, Inbred Strains; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D019089:Stem Cell Factor; D014916:Whole-Body Irradiation
D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; D019089:Stem Cell Factor