Amelioration of acute oral mucositis by Keratinocyte growth factor: fractionated irradiation

Abstract

Purpose : The aim of the present study was to quantify the protective efficacy of recombinant human keratinocyte growth factor (rHuKGF) in oral mucosa. Methods and Materials : 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.