MRI OF HUMAN TUMOR XENOGRAFTS IN-VIVO - PROTON RELAXATION-TIMES AND EXTRACELLULAR TUMOR VOLUME

Proton T-1 and T-2 differ substantially between tumors, but the tumor properties causing heterogeneity in T-1 and T2 have not been fully rec ognized. The purpose of the study reported here was to investigate whe ther differences in T-1 and T-2 between tumors are mainly a consequenc e of differences in the fractional volume of the extracellular compart ment. The study was performed using a single human tumor xenograft lin e showing large naturally occurring intratumor heterogeneity in the si ze of the extracellular compartment. The size of the extracellular com partment was calculated from the volume and the density of the tumor c ells. Cell volume was measured by an electronic particle counter. Cell density was determined by stereological analysis of histological prep arations. T-1 and T-2 were measured by MRI in vivo both in the absence and presence of Gd-DTPA. Two spin-echo pulse sequences were used, one with a repetition time (TR) of 600 ms and echo times (TEs) of 20, 40, 60, and 80 ms and the other with a TR of 2,000 ms and TEs of 20, 40, 60, and 80 ms. Measurements of T-1 and T-2 in the presence of Gd-DTPA were performed in a state of semi-equilibrium between uptake and clear ance of Gd-DTPA. MR-images and histological preparations of tumor subr egions homogeneous in extracellular volume were analysed in pairs. The extracellular volume differed between tumor subregions from 5 to 70%. T-1 and T-2 measured in the absence of Gd-DTPA differed between tumor subregions by a factor of approximately 1.5 and increased with increa sing extracellular volume. The relative decrease in T-1 caused by Gd-D TPA, represented by (T-1 (control)- T-1 (Gd-DTPA))/T-1 (control), also increased with increasing extracellular volume. The relative decrease in T-2 did not change significantly as the extracellular volume incre ased. These observations strongly suggest that the size of the extra-c ellular compartment is a major determinant of proton T(1)s and T(2)s o f tumors, possibly because the ratios of free to structured and free t o bound water increase with increasing extracellular tumor volume.