Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor.
As part of phase I/II clinical trials of granulocyte colony-stimulating factor (G-CSF), the pharmacokinetics was studied. To determine the optimal way of abrogating the neutropenia caused by melphalan, patients received G-CSF and melphalan on several schedules. The half-life (t 1/2) of elimination of G-CSF was in the range 1.3 to 4.2 hours and was prolonged at higher doses, suggesting that one clearance mechanism becomes saturated at doses greater than 10 micrograms/kg, When a continuous subcutaneous (SC) infusion was administered for five days, a rapid reduction in serum G-CSF levels occurred during the last two days of the infusion, indicating that an additional clearance mechanism was induced. When a continuous infusion of G-CSF was administered after melphalan, serum G-CSF levels remained constant for a longer period of time but did decrease during the second phase of a biphasic neutrophil response. In another clinical trial, G-CSF was administered after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). In these patients, the G-CSF levels did not decrease while the patients were neutropenic. These results show that increased neutrophil levels are associated with increased clearance of G-CSF. This may be one of the negative feedback mechanisms involved in maintaining neutrophil homeostasis in normal and disease states.
Layton
J E
JE
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia.
Hockman
H
H
Sheridan
W P
WP
Morstyn
G
G
D002454:Cell Differentiation; D003115:Colony-Stimulating Factors / Q000096:biosynthesis* / Q000097:blood / Q000493:pharmacokinetics; D016179:Granulocyte Colony-Stimulating Factor; D006098:Granulocytes / Q000502:physiology*; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000187:drug effects; D008558:Melphalan / Q000008:administration & dosage; D009504:Neutrophils / Q000187:drug effects
D003115:Colony-Stimulating Factors; D016179:Granulocyte Colony-Stimulating Factor; D008558:Melphalan