REGIONAL [MISONIDAZOLE-C-14 DISTRIBUTION IN EXPERIMENTAL RT-9-BRAIN TUMORS

Abstract

Regional [14C]misonidazole-derived radioactivity (MISO*) was measured by quantitative autoradiography in experimental RT-9 brain tumors 0.5, 2 and 4 h after an i.v. bolus (25 mg) and constant infusion (10 mg/h). Misonidazole (MISO) concentration in plasma and brain was also measured by high-pressure liquid chromatography; the brain/plasma MISO ratio ranged from 0.5-0.7. MISO equivalents were calcualted from tissue or plasma 14C radioactivity and [14C]MISO specific activity data. The MISO/MISO equivalents ratio, which represents the nonmetabolized fraction of [14C]MISO*, fell gradually in plasma (0.89 at 4 h) and more rapidly in brain (0.67 at 4 h) and tumor (0.30 at 4 h). MISO* distributed uniformly throughout the brain at all 3 time periods. MISO* distribution in tumor was variable, and tumor concentrations relative to that in brain increased with time. The average tumor/brain MISO* ratio was 1.3, 1.7 and 2.6 at 0.5, 2 and 4 h, respectively, which suggests tumor uptake and binding of MISO or, more likely, MISO-derived 14C-labeled metabolites. MISO* distribution in tumor tissue was strikingly heterogeneous at 4 h, resulting in an average high/low tumor activity ratio of 4/1 and an average high tumor/brain ratio of 5/1. Tumor regions with high MISO* activity correlated in part to viable-appearing cells around necrotic foci.