title: Bactericidal/permeability-increasing protein (rBPI21) and fluoroquinolone mitigate radiation-induced bone marrow aplasia and death.
abstract: Identification of safe, effective treatments to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the U.S. Food and Drug Administration has yet to approve any agent for a mass-casualty radiation disaster. Because patients undergoing hematopoietic stem cell transplantation undergo radiation treatment that produces toxicities similar to radiation-disaster exposure, we studied patients early after such treatment to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity and tested this idea in mice. A single 7-Gy radiation dose, which killed 95% of the mice by 30 days, was followed 24 hours later by twice-daily, subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum antibacterial activity, including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle plus fluoroquinolone, the combined rBPI21 plus fluoroquinolone treatment improved survival, accelerated hematopoietic recovery, and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 plus fluoroquinolone initiated 24 hours after lethal irradiation, combined with their established favorable bioactivity and safety profiles in critically ill humans, suggests the potential clinical use of this radiation mitigation strategy and supports its further evaluation.
authors: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Eva C
authors: EC
authors: Guinan
authors: Christine M
authors: CM
authors: Barbon
authors: Leslie A
authors: LA
authors: Kalish
authors: Kalindi
authors: K
authors: Parmar
authors: Jeff
authors: J
authors: Kutok
authors: Christy J
authors: CJ
authors: Mancuso
authors: Liat
authors: L
authors: Stoler-Barak
authors: Eugénie E
authors: EE
authors: Suter
authors: Janice D
authors: JD
authors: Russell
authors: Christine D
authors: CD
authors: Palmer
authors: Leighanne C
authors: LC
authors: Gallington
authors: Annie
authors: A
authors: Voskertchian
authors: Jo-Anne
authors: JA
authors: Vergilio
authors: Geoffrey
authors: G
authors: Cole
authors: Kaya
authors: K
authors: Zhu
authors: Alan
authors: A
authors: D'Andrea
authors: Robert
authors: R
authors: Soiffer
authors: Jerrold P
authors: JP
authors: Weiss
authors: Ofer
authors: O
authors: Levy
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001772:Blood Cell Count; D001798:Blood Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000097:blood / Q000150:complications; D004731:Endotoxins / Q000378:metabolism; D000077422:Enrofloxacin; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007413:Intestinal Mucosa / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000097:blood / Q000150:complications; D009929:Organ Size / Q000187:drug effects / Q000528:radiation effects; D011832:Radiation Injuries / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D016019:Survival Analysis; D014916:Whole-Body Irradiation
chemical_list: D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D016207:Cytokines; D004731:Endotoxins; D024841:Fluoroquinolones; D018836:Inflammation Mediators; C021623:bactericidal permeability increasing protein; D000077422:Enrofloxacin