Measurement of the extracellular volume of human melanoma xenografts by contrast enhanced magnetic resonance imaging

Abstract

The magnitude of the extracellular volume fraction (ECV) of tumors is of importance for the transport of macromolecular therapeutic agents from the vessel wall to the tumor cells. The aim of this study was to develop a method for measurement of tumor ECV by contrast enhanced MRI. Tumors of two human amelanotic melanoma xenograft lines (A-07 and R-18) grown intradermally in Balb/c nu/nu mice were used as model system, and muscle tissue was used as control. The renal arteries of the mice were ligated prior to i.v. administration of Gd-DTPA, and an MRI protocol for calculating Gd-DTPA concentration in tissue was followed. ECV was calculated from the Gd-DTPA concentrations in the tissue and in a plasma sample. In muscle tissue, the concentration reached a constant level after 1 min and the ECV was calculated to be 0.12 (± 0.01), consistent with values reported in the literature. Individual tumors showed large differences in the uptake of Gd-DTPA. The Gd-DTPA concentration in the tissue at 40 min after the Gd-DTPA administration was used to calculate tumor ECV. The ECV was found to differ significantly among regions of individual tumors and among individual tumors. The ECV ranged from 0.075 to 0.33 for A-07 tumors and from 0.016 to 0.097 for R-18 tumors. The intra- and intertumor heterogeneity in ECV was confirmed by histologic findings, showing that contrast enhanced MRI is suitable for non-invasive studies of the ECV in experimental tumors without necrosis.