The Influence of Cytotoxicity of Macromolecules and of VEGF Gene Modulated Vascular Permeability on the Enhanced Permeability and Retention Effect in Resistant Solid Tumors
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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.
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- 1.T. Minko, P. Kopečková, V. Pozharov, and J. Kopeček. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J. Contr. Rel. 54:223–233 (1998).Google Scholar
- 2.T. Minko, P. Kopečková, and J. Kopeček. Chronic exposure to HPMA copolymer-bound adriamycin does not induce multidrug resistance in a human ovarian carcinoma cell line. J. Contr. Rel. 59:133–148 (1999).Google Scholar
- 3.T. Minko, P. Kopečková, and J. Kopeček. Comparison of the anticancer effect of free and HPMA copolymer-bound adriamycin in human ovarian carcinoma calls. Pharm. Res. 16:986–996 (1999).Google Scholar
- 4.T. Minko, P. Kopečková, and J. Kopeček. Efficacy of the chemotherapeutic action of HPMA coppolymer bound doxorubicin in a solid tumor model of ovarian carcinoma. Int. J. Cancer, 86:108–117 (2000).Google Scholar
- 5.Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 46:6387–6392 (1986).Google Scholar
- 6.H. Maeda, L. M. Seymour, and Y. Miyamoto. Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chem. 3:351–362 (1992).Google Scholar
- 7.Y. Noguchi, J. Wu, R. Duncan, J. Strohalm, K. Ulbrich, T. Akaike, and H. Maeda. Early phase tumor accumulation of macromolecules: A great difference in clearance rate between tumor and normal tissues. Jpn. J. Cancer Res. 89:307–314 (1998).Google Scholar
- 8.J. Kopeček, P. Rejmanová, J. Strohalm, K. Ulbrich, B. Ríhová, V. ChytrÝ , J. B. Lloyd, and R. Duncan. Synthetic polymeric drugs. U.S. Pat. 5,037,883 (Aug. 6, 1991).Google Scholar
- 9.V. G. Omelyanenko, P. Kopečová, C. Gentry, J.-G. Shiah, and J. Kopeček. HPMA copolymer-anticancer drug-OV-TL16 antibody conjugates. 1. Influence of the methods of synthesis on the binding affinity to OVCAR-3 ovarian carcinoma cells in vitro. J. Drug Target. 3:357–373 (1996).Google Scholar
- 10.V. Omelyanenko, P. Kopečková, C. Gentry, and J. Kopeček. Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate. J. Contr. Rel. 53:25–37 (1998).Google Scholar
- 11.E. Tischler, R. Mitchell, T. Hartman, M. Silva, D. Gospodarowicz, J. C. Fiddes, and J. A. Abraham. The human gene for vascular endothelial growth factor: Multiple protein forms are encoded through alternative exon aplicing. J. Biol. Chem. 266:11947–11954 (1991).Google Scholar
- 12.B. C. Trauth, C. Klas, A. M. Peters, S. Matzku, P. Moller, W. Falk, K. M. Debatin, and P. H. Krammer. Monoclonal antibody· mediated tumor regression by induction of apoptosis. Science. 245:301–305 (1989).Google Scholar
- 13.H. F. Dvorak, J. A. Nagy, J. T. Dvorak, and A. M. Dvorak. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol. 133:95–109 (1988).Google Scholar
- 14.F. Yuan, M. Dellian, D. Fukumura, M. Leuning, D. A. Berk, V. P. Torchilin, and R. K. Jain. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55:3752–3756 (1995).Google Scholar
- 15.L. E. Benjamin, R. Goljanin, A. Irin, D. Pode, and E. Keshet. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Invest. 103:159–165 (1999).Google Scholar
- 16.S. Mesiano, N. Ferrara, and R. B. Jaffe. Role of vascular endothelial growth factor in ovarian cancer. Am. J. Pathol. 153:1249–1256 (1998).Google Scholar
- 17.J.-G. Shiah, Y. Sun, C. M. Peterson, and J. Kopeček. Biodistribution of free and N-(2-hydroxypropyl)methacrylamide copolymer-bound mesochlorin e6 and adriamycin in nude mice bearing human ovarian carcinoma OVCAR-3 xenografts. J. Contr. Rel. 61:145–157 (1999).Google Scholar
- 18.Y. Tabata, T. Kawai, Y. Murakami, and Y. Ikada. Electric charge influence of dextran derivatives on their tumor accumulation after intravenous injection. Drug Delivery 4:213–221 (1997).Google Scholar
- 19.S. K. Hobbs, W. L. Monsky, F. Yuan, W. G. Roberts, L. Griffith, V. P. Torchilin, and R. K. Jain. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95:4607–4612 (1998).Google Scholar
- 20.Y. Murakami, Y. Tabata, and Y. Ikada, Effect of the molecular weight of water-soluble polymers on accumulation at an inflammatory site following intravenous injection. Drug Delivery 3: 231–238 (1996).Google Scholar
- 21.Z-R. Lu, P. Kopečková, Z. Wu, and J. Kopeček. Synthesis of semitelechelic poly[N-(2-hydroxypropyl)methacrylamide] by radical polymerization in the presence of alkyl mercaptans. Macromol. Chem. Phys. 200:2022–2030 (1999).Google Scholar
- 22.Y. Takakura and M. Hashida. Macromolecular carrier systems for targeted drug delivery: pharmacokinetic consideration on biodistribution. Pharm. Res. 13:820–831 (1996).Google Scholar
- 23.H. M. Sowter, A. N. Corps, A. L. Evans, D. E. Clark, D. S. Charnok-Jones, and S. K. Smith. Expression and localization of the vascular endothelial growth factor family in ovarian epithelial tumors. Lab. Invest. 77:607–614 (1997).Google Scholar
- 24.N. Ferrara and W. J. Henzel. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161:851–858 (1989).Google Scholar
- 25.N. Ravindranath, L. Little-Ihrig, H. S. Phillips, N. Ferrara, and A. J. Zeleznik. Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology 131:254–260 (1992).Google Scholar
- 26.T. A. Olson, D. Mohanraj, L. F. Carson, and S. Ramakrishnan. Vascular permeability gene expression in normal and neoplastic human ovaries. Cancer Res. 54:276–280 (1994).Google Scholar
- 27.D. R. Senger, C. A. Perruzzi, J. Feder, and H. F. Dvorak. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 46:5629–5632 (1986).Google Scholar
- 28.B. Berse, L. F. Brown, L. Van De Watter, A. Papadopoulos-Sergiou, C. A. Perruzzi, E. J. Manseau, H. F. Dvorak, and D. R. Senger. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol. Biol. Cell 3:211–220 (1992).Google Scholar
- 29.H. Maeda, J. Wu, S. Tamaka, and T. Akaike. Modulation of tumor vascular permeability and EPR effect for macromolecular therapeutics. In 9th International Symposium on Recent Advances in Drug Delivery Systems, February 22¶ 25, 1999, Salt Lake City, USA, p. 114–117.Google Scholar
- 30.J. Lankelma, H. Dekker, R. F. Luque, S. Luykx, K. Hoekman, P. van der Valk, P. J. van Diest, and H. M. Pinedo. Doxorubicin gradients in human breast cancer. Clin. Cancer Res. 5:1703–1707 (1999).Google Scholar