In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice.
The purpose of this study was to investigate the in vivo radioprotective effects of recombinant human granulocyte colony stimulating factor (rhG-CSF) in lethally irradiated BALB/c mice. We initially analyzed the effects of increasing doses of rhG-CSF on survival of mice receiving 700 cGy (LD100/30) single dose total body irradiation (TBI). While 1 microgram/kg to 100 micrograms/kg doses of rhG-CSF were not radioprotective, a dose-dependent radioprotection was observed at 200 micrograms/kg to 4,000 micrograms/kg rhG-CSF. We next compared four different rhG-CSF treatment regimens side by side for their radioprotective effects in LD100/30 irradiated mice. One hundred percent of control mice receiving phosphate buffered saline died within 21 days after TBI with a median survival of 14 days. The median survival was prolonged to 20 days and the actuarial 60-day survival rate was increased to 27% when mice received 2,000 micrograms/kg rhG-CSF 24 hours before TBI (P = .0002; Mantel-Peto-Cox). Similarly, the median survival time was prolonged to 24 days and the actuarial 60-day survival rate was increased to 33%, when mice were given 2,000 micrograms/kg rhG-CSF 30 minutes before TBI. Optimal radioprotection was achieved when 2,000 micrograms/kg rhG-CSF was administered in two divided doses of 1,000 micrograms/kg given 24 hours before and 1,000 micrograms/kg given 30 minutes before TBI. This regimen prolonged the median survival time of LD100/30 irradiated mice to more than 60 days and increased the actuarial 60-day survival rate to 62% (P = .0001; Mantel-Peto-Cox). By comparison, no survival advantage was observed when mice received rhG-CSF 24 hours post-TBI. Similar radioprotective effects were observed when mice were irradiated with 650 cGy (LD80/30). The presented findings provide conclusive evidence that rhG-CSF has significant in vivo radioprotective effects for mice receiving LD100/30 or LD80/30 TBI.
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis.
F M
FM
Uckun
L
L
Souza
K G
KG
Waddick
M
M
Wick
C W
CW
Song
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis / Q000187:drug effects*; D051379:Mice; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D016019:Survival Analysis; D013997:Time Factors
D003115:Colony-Stimulating Factors; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor