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      The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting

      Advances in Enzyme Regulation

      Elsevier BV

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          Most cited references 34

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          Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

           D Senger,  S Galli,  A. Dvorak (1983)
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            Vascular permeability factor, an endothelial cell mitogen related to PDGF.

            Vascular permeability factor (VPF) is a 40-kilodalton disulfide-linked dimeric glycoprotein that is active in increasing blood vessel permeability, endothelial cell growth, and angiogenesis. These properties suggest that the expression of VPF by tumor cells could contribute to the increased neovascularization and vessel permeability that are associated with tumor vasculature. The cDNA sequence of VPF from human U937 cells was shown to code for a 189-amino acid polypeptide that is similar in structure to the B chain of platelet-derived growth factor (PDGF-B) and other PDGF-B-related proteins. The overall identity with PDGF-B is 18%. However, all eight of the cysteines in PDGF-B were found to be conserved in human VPF, an indication that the folding of the two proteins is probably similar. Clusters of basic amino acids in the COOH-terminal halves of human VPF and PDGF-B are also prevalent. Thus, VPF appears to be related to the PDGF/v-sis family of proteins.
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              Early Phase Tumor Accumulation of Macromolecules: A Great Difference in Clearance Rate between Tumor and Normal Tissues

              The objective of this study was to investigate the molecular weight (MW) and time‐dependence of the phenomenon termed “the enhanced permeability and retention”(EPR) effect in solid tumor, in particular to determine and define the early phase accumulation of macromolecules in tumor and normal tissues and the relationship between blood concentration and tissue clearance. As a model, radioiodinated N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymers of MW ranging from 4.5 K to 800 K were administered i.v. to mice bearing sarcoma 180 tumor. Within 10 min all HPMA copolymers accumulated effectively in the tumor regardless of MW (1.0–1.5% of injected dose per g of tumor). However, higher MW copolymers (>50 K) showed significantly increased tumor accumulation after 6 h, while the lower MW copolymers (<40 K) were cleared rapidly from tumor tissue due to rapid diffusion back into the bloodstream. Blood clearance was also MW‐dependent; the lower MW copolymers displayed rapid clearance, with kidney radioactivity of the copolymers of MW <20 K representing 24% of injected dose per g kidney at 1 min after i.v. administration. Within 10 min these copolymers passed through the kidney and were excreted in the urine. Higher MW copolymers consistently showed kidney levels of 3–5% dose per g kidney in the early phase with no time‐dependent accumulation in kidney. There was also no progressive accumulation in muscle or liver, regardless of polymer MW. These results suggest the “EPR effect” in solid tumor primarily arises from in the difference in clearance rate between the solid tumor and the normal tissues after initial penetration of the polymers into these tissues.
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                Author and article information

                Journal
                Advances in Enzyme Regulation
                Advances in Enzyme Regulation
                Elsevier BV
                00652571
                May 2001
                May 2001
                : 41
                : 1
                : 189-207
                Article
                10.1016/S0065-2571(00)00013-3
                © 2001

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