Regional measurements of [14C]misonidazole distribution and blood flow in subcutaneous RT-9 experimental tumors

Abstract

Regional [14C]misonidazole-derived radioactivity (MISO*) was measured by quantitative autoradiography in s.c. RT-9 experimental tumors 0.5, 2, and 4 h after an i.v. bolus (25 mg) and constant infusion (10 mg/h) in rats. Misonidazole (MISO) concentration in plasma, tumor, and other tissues was also measured by high-pressure liquid chromatography. The distribution of MISO* in the tumors always resulted in a characteristic pattern with high peripheral and low central values. The high-activity regions in the tumor rim achieved tissue: plasma MISO* activity ratios of 0.97 and 2.2 by 0.5 and 4 h, respectively; for central tumor regions, this ratio was 0.20 and 0.32 for the same periods, respectively. The limited distribution of MISO* to central tumor regions could be correlated to low values of blood flow (measured with [131I]iodoantipyrine) and to diffusion from peripheral tumor regions. Low blood flow in the central regions of these tumors will significantly limit the distribution of MISO and other drugs to viable-appearing cells in these areas and could account in part for the failures of chemotherapy in certain solid tumors. Pharmacokinetic modeling indicates that 1 to 9 h may be necessary for MISO concentrations in some tumor regions to reach 50% of that in plasma.