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Acceleration of hematopoietic reconstitution with a synthetic cytokine
(SC-55494) after radiation-induced bone marrow aplasia
AM Farese, F Herodin, JP McKearn, C Baum, E Burton and TJ MacVittie
Armed Forces Radiobiology Research Institute, Bethesda, MD, USA.
The synthetic cytokine (Synthokine) SC-55494 is a high-affinity
interleukin-3 (IL-3) receptor ligand that stimulates greater in vitro
multilineage hematopoietic activity than native IL-3, while inducing no
significant increase in inflammatory activity relative to native IL-3. The
aim of this study was to investigate the in vivo hematopoietic response of
rhesus monkeys receiving Synthokine after radiation-induced marrow aplasia.
Administration schedule and dose of Synthokine were evaluated. All animals
were total-body irradiated (TBI) with 700 cGy 60Co gamma radiation on day
0. Beginning on day 1, cohorts of animals (n = 5) received Synthokine
subcutaneously (SC) twice daily with 25 micrograms/kg/d or 100
micrograms/kg/d for 23 days or 100 micrograms/kg/d for 14 days. Control
animals (n = 9) received human serum albumin SC once daily at 15
micrograms/kg/d for 23 days. Complete blood counts were monitored for 60
days postirradiation and the durations of neutropenia (NEUT; absolute
neutrophil count [ANC] < 500/microL) and thrombocytopenia (THROM;
platelet count < 20,000/microL) were assessed. Synthokine significantly
(P < .05) reduced the duration of THROM versus the HSA-treated animals
regardless of dose or protocol length. The most striking reduction was
obtained in the animals receiving 100 micrograms/kg/d for 23 days (THROM =
3.5 v 12.5 days in HSA control animals). Although the duration of NEUT was
not significantly altered, the depth of the nadir was significantly
lessened in all animal cohorts treated with Synthokine regardless of dose
versus schedule length. Bone marrow progenitor cell cultures indicated a
beneficial effect of Synthokine on the recovery of granulocyte-macrophage
colony-forming units that was significantly higher at day 24 post-TBI in
both cohorts treated at 25 and 100 micrograms/kg/d for 23 days relative to
the control animals. Plasma pharmacokinetic parameters were evaluated in
both normal and irradiated animals. Pharmacokinetic analysis performed in
irradiated animals after 1 week of treatment suggests an effect of
repetitive Synthokine schedule and/or TBI on distribution and/or
elimination of Synthokine. These data show that the Synthokine, SC55 94,
administered therapeutically post-TBI, significantly enhanced platelet
recovery and modulated neutrophil nadir and may be clinically useful in the
treatment of the myeloablated host.
Volume 87,
Issue 2,
pp. 581-591,
01/15/1996
Copyright © 1996 by The American Society of Hematology
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