The influence of cytotoxicity of macromolecules and of VEGF gene modulatedvascular permeability on the enhanced permeability and retention effect inresistant solid tumors

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.