Effects of misonidazole, irradiation and hyperthermia on lysosomal enzyme activity in mouse tumours

Abstract

Male C 3H mice bearing transplanted tumours were treated with hyperthermia, γ-irradiation and the radiosensitising drug misonidazole. The activity of tumour lysosomal acid phosphatase and β-glucuronidase was determined using quantitative cytochemical techniques which measure both lysosomal membrane permeability and enzyme activity. Misonidazole (0.5 mg/g) had no effect on the membrane permeability or enzyme activity of tumour lysosomes 1 hr after injection; but 25 hr after the drug treatment the permeability of the lysosomal membrane to the substrate was increased to 1.7 times control. Increases in the lysosomal enzyme activity and membrane permeability were, however, observed 1 hr after combined treatment with misonidazole and irradiation, although neither the drug nor irradiation given alone affected the lysosomes 1 hr after treatment. Twenty-five hours after treatment of tumours with 0.5 mg/g misonidazole given 25 min before irradiation of tumours with 1 krad, permeability of the lysosomal membrane had increased to 2.3 times the control. The effects of the irradiation and the radiosensitisers were thus synergistic. Hyperthermic treatment of tumours at 43°C for 1 hr caused increases in the lysosomal membrane permeability and enzyme activity measured immediately after exposure, but misonidazole reduced both membrane permeability and enzyme activity. These experiments have demonstrated that misonidazole and irradiation act synergistically to cause increased lysosomal activity, but that misonidazole depresses the effect of hyperthermia on lysosomes.