Response of mouse oral mucosa to repeated doses of bleomycin

Bleomycin (BLM) applied at systemically tolerable doses induces denudation of tongue mucosa in the C3H-Neuherberg mouse strain. The dose-incidence curve after single injections has a sigmoid shape with an ED50 of 17.5 mg/kg. In contrast, the dose-response curves to repeated (two, five and 10) drug injections follow triphasic shapes and show dose-effect inversions. The effect initially increases with dose to a maximum of 70-100% at 2 x 7, 5 x 2, and 10 x 0.9 mg/kg. A marked decrease in response is observed at higher doses with a nadir of 10-30% after 2 x 11 mg/kg, 5 x 4 to 5 x 5 mg/kg and 10 x 2 mg/kg, followed by a second rise when dose is further increased. These clinical results were confirmed in a histological study. Variation of the time interval between two drug injections caused marked fluctuations in the treatment efficacy. A clear increase in drug response was induced by splitting total drug doses of 6, 14 or 22 mg/kg, the maximum effect (100%) was seen at intervals of 2 h, 0.5-1 h and 0.25 h between two injections of 3, 7 or 11 mg/kg, respectively. At longer intervals of up to 6 h, a dose-dependent decrease in drug efficacy resulted in an inverse dose-effect. Original tissue tolerance to BLM was restored only in the 2 x 3 mg/kg arm but was still elevated in the other arms after 96 h. The results can be plausibly explained by the dose-dependent induction of detoxifying processes.