title: Protected graft copolymer-formulated fibroblast growth factors mitigate the lethality of partial body irradiation injury.
abstract: We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.
authors.affiliation: PharmaIN Corp., Bothell, Washington, United States of America.
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Castillo
authors.affiliation: PharmaIN Corp., Bothell, Washington, United States of America.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishimoto-Ashfield
authors.affiliation: PharmaIN Corp., Bothell, Washington, United States of America.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Jones
authors.affiliation: Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Kasim K
authors.initials: KK
authors.lastname: Kabirov
authors.affiliation: Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zakharov
authors.affiliation: Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, United States of America.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Lyubimov
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D051519:Fibroblast Growth Factor 4 / Q000009:adverse effects / Q000627:therapeutic use; D051523:Fibroblast Growth Factor 7 / Q000009:adverse effects / Q000627:therapeutic use; D005346:Fibroblast Growth Factors / Q000009:adverse effects / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D053208:Kaplan-Meier Estimate; D007928:Lethal Dose 50; D008297:Male; D008810:Mice, Inbred C57BL; D011107:Polylysine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011833:Radiation Injuries, Experimental / Q000628:therapy*
chemical_list: C496446:Fgf4 protein, mouse; C496454:Fgf7 protein, mouse; D051519:Fibroblast Growth Factor 4; D011108:Polymers; D051523:Fibroblast Growth Factor 7; D011107:Polylysine; D005346:Fibroblast Growth Factors