Relevance of keratinocyte growth factor administration protocol for amelioration of acute radiation-induced oral mucositis

Keratinocyte growth factor (rHuKGF) significantly reduces oral mucositis in the mouse tongue model. The present study was initiated to optimise the KGF treatment protocol, using mucosal ulceration as the endpoint. Fractionated irradiation with 5x3 Gy/week was followed by test irradiation on day 7 or 14. In the first experiment, 1 or 3 injections (5 mg/kg/day) were applied either before the onset of fractionation (day -3, day -2, days -3 to -1) or over the first weekend (day +4. day +5, days +4 to +6), followed by one further injection at the subsequent weekend (day +4/day +11). In a second experiment, graded doses of KGF (1-30 mg/kg) were administered on days -3, +4 +11. After 5 or 10 fractions of 3 Gy, the ED50 for test irradiation was 5.1±1.9 Gy or 5.7±1.5 Gy, respectively, compared to 10.7±1.0 Gy for test irradiation alone. This indicates effective repopulation in week 2. KGF administration over the weekend before irradiation plus on day +4 increased the ED50 to 12.1-12.3 Gy, independent of the number of injections. Injections over the first weekend plus on day +11 resulted in ED50 values of 12.8-14.3 Gy, again independent of KGF injection number. In the dose optimisation study, KGF doses as low as 1 mg/kg resulted in a significant increase in ED50s for all days studied. Maximum efficacy was found with doses of 15-22.5 mg/kg, with ED50 values of 12.1±1.3 Gy (day -3), 14.4±1.3 Gy (day +4), and 13.7 Gy (day +11) Higher KGF doses did not result in a further increase in ED50. In conclusion, a marked increase in oral mucosal radiation tolerance by KGF was observed in all protocols tested. Repeated injections on consecutive days did not increase the effect. A significant effect of dose per injection was demonstrated, with optimum doses (mouse tongue mucosa) of 15-22.5 mg/kg