RhG-CSF Improves Radiation-induced Myelosuppression and Survival in the Canine Exposed to Fission Neutron Irradiation

Abstract

Fission-neutron radiation damage is hard to treat due to its critical injuries to hematopoietic and gastrointestinal systems, and so far few data are available on the therapeutic measures for neutron-radiation syndrome. This study was designed to test the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in dogs which had received 2.3 Gy mixed fission-neutron-γ irradiation with a high ratio of neutrons (~90%). Following irradiation, rhG-CSF treatment induced 100% survival versus 60% in controls. Only two of five rhG-CSF-treated dogs experienced leukopenia (white blood cells [WBC] count < 1.0 × 10(9)/L) and neutropenia (neutrophil [ANC] count < 0.5 × 10(9)/L), whereas all irradiated controls displayed a profound period of leukopenia and neutropenia. Furthermore, administration of rhG-CSF significantly delayed the onset of leukopenia and reduced the duration of leucopenia as compared with controls. In addition, individual dogs in the rhG-CSF-treated group exhibited evident differences in rhG-CSF responsiveness after neutron-irradiation. Finally, histopathological evaluation of the surviving dogs revealed that the incidence and severity of bone marrow, thymus and spleen damage decreased in rhG-CSF-treated dogs as compared with surviving controls. Thus, these results demonstrated that rhG-CSF administration enhanced recovery of myelopoiesis and survival after neutron-irradiation.

The Gottingen Minipig Is a Model of the Hematopoietic Acute Radiation Syndrome: G-Colony Stimulating Factor Stimulates Hematopoiesis and Enhances Survival From Lethal Total-Body γ-Irradiation

“…In NHPs, a 38% increase in survival following a 50% lethal dose of total body irradiation was observed (6). In dogs, G-CSF improved survival by 40–80% in the lethal dose range 3.6 – 5.0 Gy and by 40% after irradiation with 2.3 Gy mixed fission neutron-gamma irradiation (3–4). Increases in survival were accompanied by stimulation of bone marrow-derived clonogenic activity in both NHPs and canines, and reduction of the duration of cytopenia and time to recovery for both neutrophils and platelets (2–6, 15–16); significant modulation of the neutrophil nadir was observed for canines irradiated at 3.5 Gy (3), but not in NHPs (6).…”

Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation

“…The use of leucocyte growth factors and medical management will likely enhance survival through recovery of hematopoietic progenitor cells and increased production of neutrophils (Monroy et al 1988; Schuening et al 1993; MacVittie et al 2005; Farese et al 2013; Farese et al 2012b; Dainiak et al 2011; Plett et al 2012; Herodin F et al 2007; Yu et al 2011; Armstrong et al 2012; Hankey et al 2015; Amgen 2015). However, there have been no studies that suggest stem cells and associated immune reconstitution are affected through the use of leukocyte growth factors.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…This is a promising study demonstrating significant efficacy in the canine model (Soligenix Inc 2016). Amifostine, G-CSF and GM-CSF have also been evaluated in the canine model, demonstrating beneficial effects against radiation injury (MacVittie et al 1990;Nothdurft et al 1992Nothdurft et al , 1997Herrera et al 1995;Kouvaris et al 2007;Li et al 2011;Yu et al 2011).…”