Pharmaceutical Research

, Volume 17, Issue 5, pp 505–514

The Influence of Cytotoxicity of Macromolecules and of VEGF Gene Modulated Vascular Permeability on the Enhanced Permeability and Retention Effect in Resistant Solid Tumors

Authors

  • Tamara Minko
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
  • Pavla Kopečkova
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
    • Department of BioengineeringUniversity of Utah
  • Vitaliy Pozharov
    • Olympus Research
  • Keith D. Jensen
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
  • Jindřich Kopeček
    • Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of Utah
    • Department of BioengineeringUniversity of Utah
Article

DOI: 10.1023/A:1007500412442

Cite this article as:
Minko, T., Kopečkova, P., Pozharov, V. et al. Pharm Res (2000) 17: 505. doi:10.1023/A:1007500412442

Abstract

Purpose. To study the influence of cytotoxicity of macromolecules,VEGF gene expression, and vascular permeability on the enhancedpermeability and retention (EPR) effect.

Methods. Mice bearing xenografts of A2780 multidrug resistant humanovarian carcinoma were treated by free doxorubicin (DOX) andN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound DOX(P(GFLG)-DOX), Texas Red (P-TR), and FITC (P-FITC). Antitumoractivity, drug distribution in tumor, vascular permeability, VEGF geneexpression, and DNA fragmentation were studied.

Results. The accumulation of free DOX led to the VEGF geneoverexpression and increased the vascular permeability, which in turnenhanced the drug accumulation in the same location. This positivefeedback loop led to a highly inhomogeneous distribution of the drugwithin the tumor. In contrast, P(GFLG)-DOX down-regulated theVEGF gene and decreased vascular permeability. This negativefeedback seemed to prevent additional drug accumulation in dead necrotictissue, resulting in a more uniform drug distribution and enhanced theantitumor activity P(GFLG)-DOX.

Conclusions. The EPR effect significantly differed for macromoleculescontaining DOX when compared to macromolecules without drug. Thecytotoxicity of P(GFLG)-DOX amplified the EPR effect, led to amore homogenous distribution of the drug, increased the average drugconcentration in tumor and augmented its efficacy.

HPMA copolymerenhanced permeability and retention effectVEGF geneantitumor activitynecrosisdoxorubicin

Copyright information

© Plenum Publishing Corporation 2000