The labelling of EMT-6 tumours in BALB/C mice with14C-misonidazole

Abstract

14C-misonidazole was injected i.p. into BALB/C mice bearing EMT-6 [mouse mammary sarcoma] tumors. Tumor and normal tissue levels of radioactivity were determined by liquid scintillation procedures for times up to 72 h after drug administration. At times longer than 8 h, levels of 14C in tumor were 2-6 times higher than 14C levels measured in other normal tissues, with the exception of liver. The levels of 14C from misonidazole retained in liver tissue were comparable to those retained in the tumors. The clearance of 14C-misonidazole from the tumors and all normal tissues could be characterized by 2 distinct phases: a rapid phase (0.7 half-life [t1/2]) followed by a much slower phase (.apprx. 50 h t1/2). The distribution of retained 14C from labeled misonidazole within tumor-bearing mice was also measured by whole animal autoradiographic techniques. This procedure confirmed the biodistribution of 14C-misonidazole determined by liquid scintillation procedures. To enhance binding to hypoxic cells in vivo, 14C-misonidazole was administered in mulitple doses over a 3-h period, simulating a prolonged exposure to the drug. The 14C from labeled misonidazole retained in tumor tissue was 4-15 times greater than that retained in normal tissues, liver tissue being again an exception. Myocardial ischemia was induced by isoproterenol treatment, and a 2-fold increase of 14C from labeled misonidazole was found in the heart tissue of mice treated by the drug compared to controls. The increased binding of 14C-misonidazole to tumor cells after prolonged exposure to the drug and the increased binding of 14C-misonidazole to ischemic heart tissue suggests that hypoxia is a factor in sensitizer adduct formation in vivo.