Evidence for a novel in vivo control mechanism of granulopoiesis: mature
cell-related control of a regulatory growth factor
JE Layton, H Hockman, WP Sheridan and G Morstyn
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria,
Australia.
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.
Volume 74,
Issue 4,
pp. 1303-1307,
09/01/1989
Copyright © 1989 by The American Society of Hematology
