title: Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity.
abstract: Filgrastim (Neupogen®, granulocyte-colony stimulating factor) is among the few countermeasures recommended for management of patients in the event of lethal total-body irradiation. Despite the plethora of studies using filgrastim as a radiation countermeasure, relatively little is known about the optimal dose schedule of filgrastim to mitigate radiation lethality. We evaluated the efficacy of filgrastim in improving 30-day survival of CD2F1 mice irradiated with a lethal dose (LD70/30) in the AFRRI cobalt-60 facility. We tested different schedules of 1, 3, 5, 10 or 16 once-daily injections of filgrastim initiated one day after irradiation. Time optimization studies with filgrastim treatment were also performed, beginning 6-48 h postirradiation. Maximum survival was observed with 3 daily doses of 0.17 mg/kg filgrastim. Survival efficacy of the 3-day treatment was compared against the conventional 16-day filgrastim treatment after irradiation in four mouse strains with varying radiation sensitivities: C3H/HeN, C57BL/6, B6C3F1 and CD2F1. Blood indices, bone marrow histopathology and colony forming unit assays were also evaluated. Filgrastim significantly increased 30-day survival (P < 0.001) with a 3-day treatment compared to 16-day treatment. Filgrastim did not prevent cytopenia nadirs, but facilitated faster recovery of white blood cells, neutrophils, red blood cells, platelets, lymphocytes and hematocrits in all four strains. Accelerated hematopoietic recovery was also reflected in faster bone marrow reconstitution and significant increase in hematopoietic progenitors (P < 0.001) in all four mouse strains. These data indicate that prompt and abbreviated filgrastim treatment has potential benefit for triage in the event of a radiological incident for treating acute hematopoietic syndrome.
authors.affiliation: a   Radiation and Nuclear Countermeasure Program, DAIT, NIAID, NIH, Bethesda, Maryland 20889.
authors.forename: Merriline
authors.initials: M
authors.lastname: Satyamitra
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Kumar
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Shukla
authors.initials: S
authors.lastname: Biswas
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Cary
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Leonora
authors.initials: L
authors.lastname: Dickson
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Venkataraman
authors.affiliation: b   Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889.
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D000069585:Filgrastim / Q000008:administration & dosage*; D006401:Hematologic Agents / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects*; D008297:Male; D051379:Mice; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D020127:Recovery of Function / Q000187:drug effects; D013045:Species Specificity; D015996:Survival Rate; D016896:Treatment Outcome; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D006401:Hematologic Agents; D011837:Radiation-Protective Agents; D000069585:Filgrastim