Amelioration of acute oral mucositis by keratinocyte growth factor: fractionated irradiation.
OBJECTIVE
The aim of the present study was to quantify the protective efficacy of recombinant human keratinocyte growth factor (rHuKGF) in oral mucosa.


METHODS
Mouse tongue mucosal ulceration was analyzed as the clinically relevant end point. Fractionated irradiation of the snout with 5 daily fractions of 3 Gy was followed by graded test doses, given to a test area of the lower tongue, on Day 7. rHuKGF was injected s.c. in daily doses of 5 mg/kg before radiotherapy, during radiotherapy, over the weekend break, or a combination. Moreover, single rHuKGF injections (5 or 15 mg/kg) were given on Day -1 or on Day 4.


RESULTS
In a single-dose control experiment, the ED50, i.e., the dose after which ulcer induction is expected in 50% of the mice, was 10.9 +/- 0.7 Gy. Fractionated irradiation without keratinocyte growth factor rendered an ED50 for test irradiation of 5.6 +/- 3.7 Gy. Keratinocyte growth factor increased the ED50 values to 7.8 +/- 3.3 Gy (Days -3 to -1, p = 0.01), 8.3 +/- 1.6 Gy (Days -4 to -2, p = 0.0008), 10.5 +/- 1.4 Gy (Days 0 to +2, p = 0.0002), 11.0 +/- 0.5 Gy (Days 0 to +4, p = 0.002), 10.6 +/- 1.4 Gy (Days +4 to +6, p = 0.0021), 10 +/- 0.07 (Days -3 to +1, p = 0.0001) or 11.0 +/- 0.02 (Days +4 to +8, p = 0.0001). This is equivalent to compensation of approximately 1.5 fractions of 3 Gy when rHuKGF is given before radiotherapy and 3-4 fractions in all other protocols by rHuKGF treatment. Single rHuKGF injections were similarly (5 mg/kg) or more (15 mg/kg) effective.


CONCLUSIONS
In conclusion, these results indicate a marked increase in oral mucosal radiation tolerance by rHuKGF, which is most pronounced if the growth factor is applied during fractionated radiotherapy. The effect seems to be based on complex mechanisms, predominantly changes in both epithelial proliferation and differentiation processes.
Dörr
Wolfgang
W
Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Medizinische Fakultät Carl Gustav Carus der Technischen Universität, Fetscherstrasse 74, D-01307 Dresden, Germany. doerr@rcs.urz.tu-dresden.de
Spekl
Kathrin
K
Farrell
Catherine L
CL
D000818:Animals; D019583:Dose Fractionation, Radiation; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D051379:Mice; D008809:Mice, Inbred C3H; D009061:Mouth Mucosa / Q000528:radiation effects; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D011878:Radiotherapy / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013280:Stomatitis / Q000188:drug therapy* / Q000209:etiology
C496454:Fgf7 protein, mouse; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors