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Abstract
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.