Microvascular permeability of normal and neoplastic tissues

A novel, noninvasive method was developed for microvascular permeability measurements in non-malignant (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in the rabbit ear chamber. Dextran of 150,000 molecular weight, tagged with fluorescein isothiocyanate (FITC), was used as a representative tracer molecule. In vivo plasma concentration of dextran was measured by photometric analysis of the plasma layer of microvessels in the ear chamber. The plasma concentration in both normal and tumor preparations rose rapidly to a steady state with a time constant of 4.06 +/- 0.2 sec, and remained relatively constant at that level for the next 2 hr (elimination time constant = 1.77 +/- 0.9 X 10(5) sec). Extravasation of macromolecules from individual microvessels into the extravascular space was measured with the same photometric technique. Interstitial diffusion coefficients and microvascular permeability coefficients were determined by fitting a one-dimensional permeability-diffusion model to the extravasation data. The diffusivity of dextran in tumor interstitium was 2.2 +/- 1.4 X 10(-8) cm2/sec (n = 6) and in granulation tissue interstitium was 6.7 +/- 4.4 X 10(-10) cm2/sec (n = 6). Microvascular permeability in tumors was 7.26 +/- 3.29 X 10(-8) cm/sec (n = 11) and in granulation tissue was 57.24 +/- 39.24 X 10(-8) cm/sec (n = 10). These results on increased permeability (8-fold; P less than 0.002) and increased diffusivity (33-fold; P less than 0.001) in tumors provide a rational basis for the use of large-molecular-weight agents in the detection and treatment of solid tumors.