Amelioration of early radiation effects in oral mucosa (mouse) by intravenous or subcutaneous administration of amifostine.

PURPOSE

To quantify the reduction of radiation-induced oral mucositis by amifostine as a function of administration route.

MATERIAL AND METHODS

Mucosal ulceration of lower mouse tongue epithelium was analyzed. Amifostine was injected at 1.8 mg/injection subcutaneously (s.c.) or intravenously (i.v.), 45 min or 10 min prior to irradiation. With single-dose irradiation, a single amifostine injection was given. During daily fractionated irradiation (5 x 3 Gy) for 1 week, amifostine was administered s.c. or i.v. twice (days 0, 3), or s.c. on all irradiation days (days 0-4). With ten fractions over 2 weeks, five s.c. injections were given in week 1 (days 0-4) or week 2 (days 7-11), or both. Two i.v. injections were given either in week 1 (days 0, 3) or week 2 (days 7, 10). All fractionation protocols were terminated by graded test doses to generate full dose-effect curves.

RESULTS

In a single-dose control experiment, the ED(50) (dose after which ulcer induction is expected in 50% of the mice) was 11.7 +/- 1.4 Gy. Intravenous application of amifostine increased the ED(50) to 14.0 +/- 1.4 Gy (p = 0.024), while s.c. administration had no significant effect. The ED(50) for test irradiation after 5 x 3 Gy was 5.8 +/- 1.4 Gy. Two s.c. or i.v. amifostine injections yielded ED(50) values of 7.2 +/- 1.1 Gy (p = 0.0984) or 7.6 +/- 1.2 Gy (p = 0.0334); five s.c. injections increased the ED(50) to 8.2 +/- 0.9 Gy (p = 0.0039). The ED(50) after 10 x 3 Gy/2 weeks was 6.6 +/- 1.8 Gy. Subcutaneous or intravenous administration of amifostine in week 1 yielded a significant increase in ED(50) to 9.4 +/- 2.5 Gy (p = 0.0099) and 10.0 +/- 2.2 Gy (p = 0.0014). By contrast, amifostine administration in week 2 had no significant effect. Administration in weeks 1 and 2 resulted in an ED(50) of 10.8 +/- 3.6 Gy (p = 0.0053).

CONCLUSION

Amifostine during daily fractionated irradiation is effective only if administered in the initial treatment phase, i.e., week 1 in the mouse. The differences in the effect in weeks 1 and 2 suggest mechanisms of action other than radical scavenging.