title: Combination therapy for radiation-induced bone marrow aplasia in nonhuman primates using synthokine SC-55494 and recombinant human granulocyte colony-stimulating factor.
abstract: 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.
authors.affiliation: Armed Forces Radiobiology Research Institute, Bethesda, MD, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: MacVittie
authors.forename: A M
authors.initials: AM
authors.lastname: Farese
authors.forename: F
authors.initials: F
authors.lastname: Herodin
authors.forename: L B
authors.initials: LB
authors.lastname: Grab
authors.forename: C M
authors.initials: CM
authors.lastname: Baum
authors.forename: J P
authors.initials: JP
authors.lastname: McKearn
mesh_terms: D000741:Anemia, Aplastic / Q000209:etiology / Q000628:therapy*; D000818:Animals; D001803:Blood Transfusion; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007377:Interleukin-3 / Q000031:analogs & derivatives; D007962:Leukocytes / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000209:etiology / Q000628:therapy; D010446:Peptide Fragments; D010455:Peptides / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000628:therapy*; D016185:Receptors, Interleukin-3 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012709:Serum Albumin / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000209:etiology / Q000628:therapy; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; D016185:Receptors, Interleukin-3; D011994:Recombinant Proteins; D012709:Serum Albumin; D016179:Granulocyte Colony-Stimulating Factor; C093340:daniplestim; D000069585:Filgrastim