Enhancement of murine intestinal stem cell survival after irradiation by keratinocyte growth factor.
Radiation-induced gastrointestinal toxicity is due in part to the killing of the clonogenic crypt cells and eventual depopulation of the villi. Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family (FGF-7), has been shown to stimulate proliferation of cells along the murine digestive tract from the foregut to the colon. Using an in vivo microcolony assay, we found that 1.0 mg/kg KGF administered intravenously (i.v.) for 3 consecutive days (2 days before, 1 day before and 2 h after irradiation) increased the number of surviving crypts by a factor of 2.6, 2.7 and 2.4 in the duodenum, jejunum and ileum, respectively, after a single-dose whole-body irradiation (10-16 Gy) (P < 0.001). Treatment of mice with KGF i.v. significantly increased the D0 of the radiation survival curves by 0.37, 0.22 and 0.36 Gy, leading to dose modification factors of 1.28, 1.16 and 1.24 for duodenal, jejunal and ileal crypt cells, respectively. Similar results were obtained with KGF administered subcutaneously. Treatment with both KGF and stem cell factor (previously shown to enhance intestinal crypt survival after total-body irradiation) increased the number of surviving crypt cells after irradiation to levels similar to that in animals treated with KGF alone. Administration of KGF for 7 consecutive days (beginning 2 days prior to irradiation) increased the LD(50/10) from 5.50 Gy/day to 5.90 Gy/day (P = 0.05) for animals irradiated with five daily fractions to a local abdominal field. These results suggest that KGF may be of clinical value in reducing radiation toxicity to the intestine.
Khan
W B
WB
Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5105, USA.
Shui
C
C
Ning
S
S
Knox
S J
SJ
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004386:Duodenum; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007082:Ileum; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*; D007421:Intestine, Small / Q000528:radiation effects*; D007583:Jejunum; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*
C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors