The influence of cytotoxicity of macromolecules and of VEGF gene modulated vascular permeability on the enhanced permeability and retention effect in resistant solid tumors.
OBJECTIVE
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.
Minko
T
T
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
Kopeckova
P
P
Pozharov
V
V
Jensen
K D
KD
Kopecek
J
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects* / Q000235:genetics*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D046911:Macromolecular Substances; D008689:Methacrylates; D051379:Mice; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000378:metabolism; D010539:Permeability; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D046911:Macromolecular Substances; D008689:Methacrylates; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate