Microvascular permeability to macromolecules in human melanoma xenografts assessed by contrast-enhanced MRI--intertumor and intratumor heterogeneity.

Several novel macromolecular anticancer agents have fallen short of expectations owing to inadequate and heterogeneous uptake in tumor tissue. In the present work, contrast-enhanced magnetic resonance imaging was used to measure the intertumor and intratumor heterogeneity in the effective microvascular permeability constant, P(eff), of an 82 kDa macromolecule in an attempt to identify possible causes of the inadequate and heterogeneous uptake. Tumors of two human melanoma xenograft lines (A-07 and R-18) were included in the study. Human serum albumin with 30 gadopentetate dimeglumine units per molecule was used as a model molecule of macromolecular therapeutic agents. P(eff) was measured in manually defined regions of interest, corresponding to a whole tumor (ROI(WHOLE)) or to subregions of a tumor (ROIs(SUB)). The P(eff) of the ROI(WHOLE) of individual tumors ranged from 1.4 x 10(-7) cm/s to 2.8 x 10(-7) cm/s (A-07) and from 7.7 x 10(-8) cm/s to 3.2 x 10(-7) cm/s (R-18). P(eff) decreased with increasing tumor volume in R-18, but was independent of tumor volume in A-07. The intratumor heterogeneity in P(eff) exceeded the intertumor heterogeneity in both tumor lines. Some ROIs(SUB) showed P(eff) values that were similar to or slightly higher than the P(eff) values of albumin in normal tissues. Our observations suggest that inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumor tissue is partly a result of low and heterogeneous microvascular permeability. However, the microvascular wall is probably not the major transport barrier to macromolecules in A-07 and R-18 tumors, as most individual tumors and individual tumor subregions showed high P(eff) values, i.e. values that are up to 10-fold higher than those of normal tissues.