The influence of cytotoxicity of macromolecules and of VEGF gene modulatedvascular permeability on the enhanced permeability and retention effect inresistant solid tumors
T. Minko et al., The influence of cytotoxicity of macromolecules and of VEGF gene modulatedvascular permeability on the enhanced permeability and retention effect inresistant solid tumors, PHARM RES, 17(5), 2000, pp. 505-514
Purpose. To study the influence of cytotoxicity of macromolecules, VEGF gen
e expression, and vascular permeability on the enhanced permeability and re
tention (EPR) effect.
Methods. Mice bearing xenografts of A2780 multidrug, resistant human ovaria
n carcinoma were treated by free doxorubicin (DOX) and N-(2-hydroxyp ropyl)
methacrylamide (HPMA) copolymer-bound DOX (P(GFLG)-DOX), Texas Red (P-TR),
and FITC (P-FITC). Antitumor activity, drug distribution in tumor, vascular
permeability, VEGF gene expression, and DNA fragmentation were studied.
Results. The accumulation of free DOX led to the VEGF gene overexpression a
nd increased the vascular permeability, which in turn enhanced the drug acc
umulation in the same location. This positive feedback loop led to a highly
inhomogeneous distribution of the drug within the turner. In contrast, P(G
FLG)-DOX down-regulated the VEGF gene and decreased vascular permeability.
This negative Feedback seemed to prevent additional drug accumulation in de
ad necrotic tissue, resulting in a more uniform drug distribution and enhan
ced the antitumor activity P(OFLG)-DOX.
Conclusions. The EPR effect significantly differed for macromolecules conta
ining DOX when compared to macromolecules without drug. The cytotoxicity of
P(GFLG)-DOX amplified the EPR effect, led to a more homogenous distributio
n of the drug, increased the average drug concentration in tumor and augmen
ted its efficacy.