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Combination therapy for radiation-induced bone marrow aplasia in nonhuman
primates using synthokine SC-55494 and recombinant human granulocyte
colony-stimulating factor
TJ MacVittie, AM Farese, F Herodin, LB Grab, CM Baum and JP McKearn
Armed Forces Radiobiology Research Institute, Bethesda, MD, USA.
Combination cytokine therapy continues to be evaluated in an effort to
stimulate multilineage hematopoietic reconstitution after bone marrow
myelosuppression. This study evaluated the efficacy of combination therapy
with the synthetic interleukin-3 receptor agonist, Synthokine- SC55494, and
recombinant methionyl human granulocyte colony-stimulating factor (rhG-CSF)
on platelet and neutrophil recovery in nonhuman primates exposed to total
body 700 cGy 60Co gamma radiation. After irradiation on day (d) 0, cohorts
of animals subcutaneously received single-agent protocols of either human
serum albumin (HSA; every day [QD], 15 micrograms/kg/d, n = 10), Synthokine
(twice daily [BID], 100, micrograms/kg/d, n = 15), rhG-CSF (QD, 10
micrograms/kg/d, n = 5), or a combination of Synthokine and rhG-CSF (BID,
100 and 10 micrograms/kg/d, respectively, n = 5) for 23 days beginning on
d1. Complete blood counts were monitored for 60 days postirradiation and
the durations of neutropenia (absolute neutrophil count < 500/microL)
and thrombocytopenia (platelet count < 20,000/microL) were assessed.
Animals were provided clinical support in the form of antibiotics, fresh
irradiated whole blood, and fluids. All cytokine protocols significantly (P
< .05) reduced the duration thrombocytopenia versus the HSA-treated
animals. Only the combination protocol of Synthokine + rhG-CSF and rhG-CSF
alone significantly shortened the period neutropenia (P < .05). The
combined Synthokine/rhG-CSF protocol significantly improved platelet nadir
versus Synthokine alone and HSA controls and neutrophil nadir versus
rhG-CSF alone and HSA controls. All cytokine protocols decreased the time
to recovery to preirradiation neutrophil and platelet values. The
Synthokine/rhG-CSF protocol also reduced the transfusion requirements per
treatment group to 0 among 5 animals as compared with 2 among 5 animals for
Synthokine alone, 8 among 5 animals for rhG-CSF, and 17 among 10 animals
for HSA. These data showed that the combination of Synthokine, SC-55494,
and rhG-CSF further decreased the cytopenic periods and nadirs for both
platelets and neutrophils relative to Synthokine and rhG-CSF monotherapy
and suggest that this combination therapy would be effective against both
neutropenia and thrombocytopenia consequent to drug- or radiation- induced
myelosuppression.
Volume 87,
Issue 10,
pp. 4129-4135,
05/15/1996
Copyright © 1996 by The American Society of Hematology
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