The influence of cytotoxicity of macromolecules and of VEGF gene modulated vascular permeability on the enhanced permeability and retention effect in resistant solid tumors

Tamara Minko, Pavla Kopečkova, Vitaliy Pozharov, Keith D. Jensen, Jindřich Kopeček

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Purpose. To study the influence of cytotoxicity of macromolecules, VEGF gene expression, and vascular permeability on the enhanced permeability and retention (EPR) effect. Methods. Mice bearing xenografts of A2780 multidrug resistant human ovarian carcinoma were treated by free doxorubicin (DOX) and N-(2-hydroxypropyl)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 and increased the vascular permeability, which in turn enhanced the drug accumulation in the same location. This positive feedback loop led to a highly inhomogeneous distribution of the drug within the tumor. In contrast, P(GFLG)-DOX down-regulated the VEGF gene and decreased vascular permeability. This negative feedback seemed to prevent additional drug accumulation in dead necrotic tissue, resulting in a more uniform drug distribution and enhanced the antitumor activity P(GFLG)-DOX. Conclusions. The EPR effect significantly differed for macromolecules containing DOX when compared to macromolecules without drug. The cytotoxicity of P(GFLG)-DOX amplified the EPR effect, led to a more homogenous distribution of the drug, increased the average drug concentration in tumor and augmented its efficacy.

Original languageEnglish (US)
Pages (from-to)505-514
Number of pages10
JournalPharmaceutical research
Volume17
Issue number5
DOIs
StatePublished - 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Keywords

  • Antitumor activity
  • Doxorubicin
  • Enhanced permeability and retention effect
  • HPMA copolymer
  • Necrosis
  • VEGF gene

Fingerprint Dive into the research topics of 'The influence of cytotoxicity of macromolecules and of VEGF gene modulated vascular permeability on the enhanced permeability and retention effect in resistant solid tumors'. Together they form a unique fingerprint.

Cite this