On the sensitisation of skin radionecrosis in mice by misonidazole at low doses

Abstract

The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .