Post treatment with an FGF chimeric growth factor enhances epithelial cell proliferation to improve recovery from radiation-induced intestinal damage.
OBJECTIVE
A fibroblast growth factor (FGF) 1-FGF2 chimera (FGFC) was created previously and showed greater structural stability than FGF1. This chimera was capable of stimulating epithelial cell proliferation much more strongly than FGF1 or FGF2 even without heparin. Therefore FGFC was expected to have greater biologic activity in vivo. This study evaluated and compared the protective activity of FGFC and FGF1 against radiation-induced intestinal injuries.


METHODS
We administered FGFC and FGF1 intraperitoneally to BALB/c mice 24 h before or after total-body irradiation (TBI). The numbers of surviving crypts were determined 3.5 days after TBI with gamma rays at doses ranging from 8 to 12 Gy.


RESULTS
The effect of FGFC was equal to or slightly superior to FGF1 with heparin. However, FGFC was significantly more effective in promoting crypt survival than FGF1 (p < 0.01) when 10 μg of each FGF was administered without heparin before irradiation. In addition, FGFC was significantly more effective at promoting crypt survival (p < 0.05) than FGF1 even when administered without heparin at 24 h after TBI at 10, 11, or 12 Gy. We found that FGFC post treatment significantly promoted 5-bromo-2'-deoxyuridine incorporation into crypts and increased crypt depth, resulting in more epithelial differentiation. However, the number of apoptotic cells in FGFC-treated mice decreased to almost the same level as that in FGF1-treated mice.


CONCLUSIONS
These findings suggest that FGFC strongly enhanced radioprotection with the induction of epithelial proliferation without exogenous heparin after irradiation and is useful in clinical applications for both the prevention and post treatment of radiation injuries.
Nakayama
Fumiaki
F
Department of Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan. f_naka@nirs.go.jp
Hagiwara
Akiko
A
Umeda
Sachiko
S
Asada
Masahiro
M
Goto
Megumi
M
Oki
Junko
J
Suzuki
Masashi
M
Imamura
Toru
T
Akashi
Makoto
M
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000627:therapeutic use*; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007583:Jejunum / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000627:therapeutic use*; D014916:Whole-Body Irradiation / Q000009:adverse effects
D011837:Radiation-Protective Agents; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D006493:Heparin; D001973:Bromodeoxyuridine