EVIDENCE FOR A NOVEL INVIVO CONTROL MECHANISM OF GRANULOPOIESIS - MATURE CELL-RELATED CONTROL OF A REGULATORY GROWTH-FACTOR

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  • 1 September 1989
    • journal article
    • research article
    • Vol. 74  (4) , 1303-1307
Abstract
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 (t1/2) 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 > 10 .mu.g/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.