Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): A review

Abstract

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event. Direct medical interventions would be necessary for all those individuals who had received substantial radiation exposures (e.g., >1 Gy). Although no drugs or products have yet been specifically approved by the United States Food and Drug Administration (US FDA) to treat the effects of acute radiation syndrome (ARS), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and pegylated G-CSF have been used off label for treating radiation accident victims. Recent threats of terrorist attacks using nuclear or radiologic devices makes it imperative that the medical community have up-to-date information and a clear understanding of treatment protocols using therapeutically effective recombinant growth factors and cytokines such as G-CSF and GM-CSF for patients exposed to injurious doses of ionizing radiation. Based on limited human studies with underlying biology, we see that the recombinants, G-CSF and GM-CSF appear to have modest, but significant medicinal value in treating radiation accident victims. In the near future, the US FDA may approve G-CSF and GM-CSF as ‘Emergency Use Authorization’ (EUA) for managing radiation-induced aplasia, an ARS-related pathology. In this article, we review the status of growth factors for the treatment of radiological/nuclear accident victims.

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

“…However, this modified recombinant unfortunately appears to be less efficacious than G-CSF in treating irradiated animals with significant skin burns (15% total body surface area skin burns) (Kiang et al 2014a). Similar to G-CSF, PEGylated G-CSF has also been used in several radiation accident victims with positive outcomes (Reeves 2014;Singh et al 2015a). In November 2015, PEGylated G-CSF was approved by the FDA for adult and pediatric human use as a radiomitigator for H-ARS (National Institute of Allergic and Infectious Diseases 2015).…”

“…The radiomitigative efficacy of G-CSF is dependent on the extent of radiation exposure, dose of G-CSF, treatment schedule in relation to irradiation, and the period of the treatment. G-CSF has been used in several radiation accident victims with proven positive outcome (Singh et al 2015a). In The instability of G-CSF at ambient temperature and the treatment plans for radiation-exposed victims in a radiological/nuclear incident scenario are issues still of concern.…”

“…Radiation therapeutics are agents administered once symptoms manifest in order to accelerate regeneration of tissue and organs Wagemaker et al 1998;Farese et al 2001Farese et al , 2013Drouet et al 2004;Herodin et al 2007;Dumont et al 2010). G-CSF, PEGylated G-CSF, GM-CSF, and cellular therapy falls under this class (Singh et al 2015a). The outcome of any given countermeasure for the purpose of limiting the risk of potential radiation lethality may depend on the time between radiation exposure and countermeasure administration.…”

Radiation Countermeasures: Current Status

“…A signal cascade is activated by phosphorylating JAK-2 leading to JAK-STAT pathway activation, ras/raf/erk pathway activation, and anti-apoptotic pathway activation. G-CSF stimulate different progenitor cells such as lymphoid progenitor, erythroid progenitor, basophil progenitor and eosinophil progenitors which further give rise to lymphocyte, erythrocyte, basophils, respectively 18 . The efficacy of G-CSF has been evaluated in mice, canines (beagle), NHPs and mini pigs 15 .…”

IL-3 and GM-CSF in combination alters protein tyrosine kinase activity of splenic macrophages in leukemic mice.

“…After confirmation of leukemia induction, all the mice from group III and IV were received rmIL-3 at the dose of 5 µg/kg/d and rmGM-CSF at the dose of 5 µg/kg/d for 4 days (ImmunoTools GmBH, Germany) [17][18][19].…”