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Factors and Mechanism of “EPR” Effect and the Enhanced Antitumor Effects of Macromolecular Drugs Including SMANCS

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Polymer Drugs in the Clinical Stage

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 519))

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References

  1. Senger, D. R., Galli, S. J., Dvorak, A. M., Perruzzi, C. A., Harvey, V. S., and Dvorak, H. F., 1983, Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983–985.

    PubMed  CAS  Google Scholar 

  2. Asano, M., Yukita, A., Matsumoto, T., Kondo, S., and Suzuki, H., 1995, Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor. Cancer Res. 55: 5296–5301.

    PubMed  CAS  Google Scholar 

  3. Maeda, H., and Matsumura, Y., 1989, Tumoritropic and lymphotropic principles of macromolecular drugs. Crit. Rev. Ther. Drug Carrier Sys. 6: 193–210.

    CAS  Google Scholar 

  4. Maeda, H., 1991, SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv. Drug Deliv. Rev. 6:181–202.

    Article  CAS  Google Scholar 

  5. Maeda, H., 1994, Polymer conjugated macromolecular drugs for tumor-specific targeting. In Polymer Site Specific Pharmacotherapy (A. J. Domb, eds.) John Wiley & Sons Ltd., New York, USA, pp. 95–116.

    Google Scholar 

  6. Maeda, H., Seymour, L., and Miyamoto, Y., 1992, Conjugation of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chem. 3: 351–362.

    Article  CAS  Google Scholar 

  7. Courtice, F. C., 1963, The origin of lipoprotein. In Lymph and Lymphatic System (H. S. Meyersen, Chairman) Charles C. Thomas, Springfield, IL, USA, pp. 89–126.

    Google Scholar 

  8. Muggia, F. M., 1999, Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin. Cancer Res. 5: 7–8.

    PubMed  CAS  Google Scholar 

  9. Folkman, J., 1971, Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182–1186.

    Article  PubMed  CAS  Google Scholar 

  10. Folkman, J., and Shing, Y., 1992, Angiogenesis, J. Biol. Chem. 267: 10931–10934.

    PubMed  CAS  Google Scholar 

  11. Maeda, H., Matsumura, Y., and Kato, H., 1988, Purification and identification of [hydroxyprolyl 3] bradykinin in ascitic fluid from a patient with gastric cancer. J. Biol. Chem. 263: 16051–16054.

    PubMed  CAS  Google Scholar 

  12. Matsumura, Y., Kimura, M., Yamamoto, T., and Maeda, H., 1988, Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn. J. Cancer Res. 79: 1327–1334.

    PubMed  CAS  Google Scholar 

  13. Matsumura, Y., Maruo, K., Kimura, M., Yamamoto, T., Konno, T., and Maeda, H., 1991, Kinin-generating cascade in advanced cancer patients and in vitro study. Jpn. J. Cancer Res. 82: 732–741.

    PubMed  CAS  Google Scholar 

  14. Wu, J., Akaike, T., and Maeda, H., 1998, Modulation of enhanced vascular permeability in tumors by bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger. Cancer Res. 58: 159–165.

    PubMed  CAS  Google Scholar 

  15. Maeda, H., Noguchi, Y., Sato, K., and Akaike, T., 1994, Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both nitric oxide scavenger and nitric oxide synthase inhibitor. Jpn. J. Cancer Res. 85: 331–334.

    PubMed  CAS  Google Scholar 

  16. Doi, K., Akaike, T., Horie, M., Noguchi, Y., Fujii, S., Beppu, T., Ogawa, M., and Maeda, H., 1996, Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth. Cancer 77: 1598–1604.

    PubMed  CAS  Google Scholar 

  17. Ferratra, N., and Henzel, W. J., 1989, Pituitary follicular cells secrete a novel heparinbinding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161: 851–858.

    Google Scholar 

  18. Rosenthal, R. A., Megyesi, J. F., Henzel, W. J., Ferrara, N., and Folkman, J., 1990, Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor. Growth Factors 4: 53–59.

    PubMed  CAS  Google Scholar 

  19. Leung, D. W., Cachianes, G., Kuang. W-J., Goeddel, D. V., and Ferrara, N., 1989, Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306–1309.

    PubMed  CAS  Google Scholar 

  20. Keck, P. J., Hauser, S. D., Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, D. T., 1989, Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246: 1309–1312.

    PubMed  CAS  Google Scholar 

  21. Reichman, H. R., Farrell, C. L, and Del Maestro, F. R., 1986, Effect of steroids and nonsteroid anti-inflammatory agents on vascular permeability in a rat glioma model. J. Neurosurg. 65: 233–237.

    PubMed  CAS  Google Scholar 

  22. Wu, J., Akaike, T., Hayashida, K., Okamoto, T., Okuyama, A., and Maeda, H., 2001, Enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases. Jpn. J. Cancer Res. 92: 439–451.

    PubMed  CAS  Google Scholar 

  23. Suzuki, M., Takahashi, T., and Sato, T., 1987, Medial regression and its functional significance in tumor-supplying host arteries. Cancer 59: 444–450.

    PubMed  CAS  Google Scholar 

  24. Skinner, S. A., Tutton, P. J. M., and O’Brien, E., 1991, Microvascular architecture of experimental colon tumors in the rats. Cancer Res. 50: 2411–2417.

    Google Scholar 

  25. Kuruppu, D., Christophi, C., Maeda, H., and O’Brien, P. E., 2002, Changes in the microvascular architecture of colorectal liver metastases following the administration of SMANCS/lipiodol. J. Surg. Res. 103: 47–54.

    Article  PubMed  CAS  Google Scholar 

  26. Matsumura, Y., and Maeda, H., 1986, 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.

    PubMed  CAS  Google Scholar 

  27. Iwai, K., Maeda, H., and Konno, T., 1984, Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Res. 44: 2115–2121.

    PubMed  CAS  Google Scholar 

  28. Noguchi, Y., Wu, J., Duncan, R., Strohalm, J., Ulbrich, K., Akaike, T., and Maeda, H., 1998, Early phase tumor accumulation of macromolecules: A great difference in clearance rate between tumor and normal tissues. Jpn. J. Cancer Res. 89: 307–314.

    PubMed  CAS  Google Scholar 

  29. Iwai, K., Maeda, H., Konno, T., Matsumura, Y., Yamashita, R., Yamasaki, K., Hirayama, S., and Miyauchi, Y., 1987, Tumor targeting by arterial administration of lipids: rabbit model with VX2 carcinoma in the liver. Anticancer Res. 7: 321–328.

    PubMed  CAS  Google Scholar 

  30. Maeda, H., Matsumoto, T., Konno, T., Iwai, K., and Ueda, M., 1984, Tailor-making of protein drugs by polymer conjugation for tumor targeting: a brief review on Smancs. J. Prot. Chem. 3: 181–193.

    Article  CAS  Google Scholar 

  31. Maeda, H., Matsumura, Y., Oda, T., and Sasamoto, K., 1986, Cancer selective macromolecular therapeutics: tailoring of antitumor protein drugs. In Protein Tailoring. for Food and Medical Uses (R. E. Feeney and J. R. Whitaker, eds.) Marcel Dekker Inc., New York, USA, pp. 353–382.

    Google Scholar 

  32. Sawa, T., Sahoo, S. K., and Maeda H., 2002, Water-soluble polymer therapeutics with special emphasis on cancer chemotherapy. In Polymers in Medicine and Biotechnology (Ashady, eds.), Am. Chem. Soc., Washington D. C., Monograph, in press.

    Google Scholar 

  33. Suzuki, M., Hori, K., Abe, Z., Saito, S., and Sato, H., 1981, A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J. Natl. Cancer Inst. 67: 663–669.

    PubMed  CAS  Google Scholar 

  34. Li, C. J., Miyamoto, Y., Kojima, Y., and Maeda, H., 1993, Augmentation of tumor delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure. Br. J. Cancer 67: 975–980.

    PubMed  CAS  Google Scholar 

  35. Maeda, H., and Yamamoto, T., 1996, Pathogenic mechanisms induced by microbial proteases in microbial infections. Biol. Chem. Hoppe-Seyler. 377: 217–226.

    PubMed  CAS  Google Scholar 

  36. Nakano, S., Mastukado, K., and Black, K. L., 1996, Increased brain tumor microvessel permeability after intracarotid bradkinin infusion is mediated by nitric oxide. Cancer Res. 56: 4027–4031.

    PubMed  CAS  Google Scholar 

  37. Hu, D. E., and Fan, T. P., 1993, [Leu8]des-Arg9-bradykinin inhibits the angiogenic effect of bradykinin and interleukin-1 in rats. Br. J. Pharmacol. 109: 14–17.

    PubMed  CAS  Google Scholar 

  38. Maeda, H., Wu, J., Okamoto, T., Maruo, K., and Akaike, T., 1999, Kallikrein-kinin in infection and cancer. Immunopharmacology. 43: 115–128.

    Article  PubMed  CAS  Google Scholar 

  39. Hori, K., Saito, S., Takahashi, H., Sato, H., Maeda, H., and Sato, Y., 2000, Tumorselective blood flow decrease induced by an angiotensin converting enzyme inhibitor, temocapril hydrochloride. Jpn. J. Cancer Res. 91: 261–269.

    PubMed  CAS  Google Scholar 

  40. Strausser, H. R., and Humes, J. L., 1975, Prostaglandin synthesis inhibition: effect on bone changes and sarcoma tumor induction in BALB/c mice. Int. J. Cancer 15: 724–730.

    PubMed  CAS  Google Scholar 

  41. Trevisani, A., Ferretti, E., Capuzzo, A., and Tomasi, V., 1980, Elevated levels of prostaglandin E 2 in Yoshida hepatoma and the inhibition of tumor growth by nonsteroidal anti-inflammatory drugs. Br. J. Cancer 41: 341–347.

    PubMed  CAS  Google Scholar 

  42. Greengberg, E. R., Baron, J. A., Freeman, D. H., Mandel, J. S. Jr, and Haile, R., 1993, Reduced risk of large-bowel adenomas among aspirin users. J. Natl. Cancer Inst. 85: 912–916.

    Google Scholar 

  43. Meyer, R. E., Shan, S., Deangelo, J., Dodge, R. K., Bonaventura, J., Ong. E. T., and Dewhirst, M. W., 1995, Nitric oxide synthase inhibition irreversibly decreases perfusion in the R3230Ac rat mammary adenocarcinoma. Br. J. Cancer 71: 1169–1174.

    PubMed  CAS  Google Scholar 

  44. Tozer, G. M., Prise, V. E., and Chaplin, D. J., 1997, Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine, Cancer Res. 57: 948–955.

    PubMed  CAS  Google Scholar 

  45. Gallo, O., Masini, E., Morbidelli, L., Franchi, A., Fini-Storchi, I., Vergari, W. A., and Ziche, M., 1998, Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J. Natl. Cancer Inst. 90: 587–596.

    Article  PubMed  CAS  Google Scholar 

  46. Garcia-Cardena, G., and Folkman, J., 1998, Is there a role for nitric oxide in tumor angiogenesis. (Editorial) J. Natl Cancer Inst. 90: 560–561.

    Article  PubMed  CAS  Google Scholar 

  47. Jackson, J. R., Seed, M. P., Kirchen, C. H., Willoughby, D. A., and Winkler, J. D., 1997, The codependence of angiogenesis and chronic inflammation. FASEB J. 11: 457–465.

    PubMed  CAS  Google Scholar 

  48. Maeda, H., Takishita, J., and Kanamaru, R., 1979, A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic. Int. J. Pept. Protein Res. 14: 81–87.

    PubMed  CAS  Google Scholar 

  49. Maeda, H., Ueda, M., Morinaga, T., and Matsumoto, T., 1985, Conjugation of poly(styrene-co-maleic acid) derivatives to antitumor protein neocarzinostatin: pronounced improvements in pharmacological properties. J. Med. Chem. 28: 455–461.

    Article  PubMed  CAS  Google Scholar 

  50. Konno, T., Maeda, H., Iwai K., Maki, S., Tashiro, S., Uchida, M., and Miyauchi, Y., 1984, Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium. Cancer 54: 2367–2374.

    PubMed  CAS  Google Scholar 

  51. Konno, T., Maeda, H., Iwai, K., Tashiro, S., Maki, S., Marinaga, T., Mochinaga, M., Hiraoka, T., and Yokoyama, I., 1983, Effect of arterial administration of highmolecular-weight anticancer agent SMANCS with lipid lymphographic agent on hepatoma: a preliminary report. Eur. J. Cancer Clin. Oncol. 19: 1053–1065.

    Article  PubMed  CAS  Google Scholar 

  52. Maki, S., Konno, T., and Maeda, H., 1985, Image enhancement in computerized tomography for sensitive diagnosis of liver cancer and semiquantitation of tumor selective drug targeting with oily contrast medium. Cancer 56: 751–757.

    PubMed  CAS  Google Scholar 

  53. Tsuchikya, K., Uchida, T., Kobayashi, M., Maeda, H., Konno, T., and Yamanaka, H., 2000, Tumor-targeted chemotherapy with SMANCS in Lipiodol for renal cell carcinoma: longer survival with larger size tumors. Urology 55: 495–500.

    Google Scholar 

  54. Maeda, H., and Miyamoto, Y., 1994, SMANCS approach — Oily formulation of protein drugs for arterial injection and oral administration. In Drug Absorption Enhancement: Concepts, Possibilities, Limitations, and Trends (A. G. De Boer, ed.) Harwood Academic Publishers, Chur, Switzerland, pp. 221–247.

    Google Scholar 

  55. Konno, T., and Maeda, H., 1987, Targeting chemotherapy of hepatocellular carcinoma: arterial administration of SMANCS/Lipiodol. In Neoplasms of the Liver (K. Okuda, K.G. Ishak, eds.), Springer-Verlag, Tokyo, Berlin, New York, pp. 343–352.

    Google Scholar 

  56. Konno, T., 1992, Targeting chemotherapy for hepatoma: arterial administration of anticancer drugs dissolved in Lipiodol. Eur. J. Cancer 28: 403–409.

    Article  PubMed  CAS  Google Scholar 

  57. Maeda, H., and Konno, T., 1997, Metamorphosis of neocarzinostatin to SMANCS: chemistry, biology, pharmacology and clinical effect of the first prototype anticancer polymer therapeutic. In Neocarzinostatin: The Past, Present, and Future of an Anticancer Drug (H. Maeda, K. Edo and N. Ishida, eds.) Springer-Verlag, Tokyo, Berlin, New York, pp. 227–267.

    Google Scholar 

  58. Sawa, T., Wu, J., Akaike, T. and Maeda H., 2000, Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue. Cancer Res. 60: 666–671.

    PubMed  CAS  Google Scholar 

  59. Fang, J., Sawa, T., Akaike, T., and Maeda, H., 2002, Tumor-Targeted Delivery of PEGConjugated D-Amino Acid Oxidase for Antitumor Therapy via Enzymatic Generation of Hydrogen Peroxide. Cancer Res. 62: 3138–3143.

    PubMed  CAS  Google Scholar 

  60. Sahoo, S. K., Sawa, T., Fang, J., Tanaka, S., Miyamoto, Y., Akaike, T., and Maeda H., 2002, Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity. Bioconjug. Chem. 13: 1031–1038.

    Article  PubMed  CAS  Google Scholar 

  61. Doi, K., Akaike, T., Fujii, S., Tanaka, S., Ikebe, S., Beppu, N., Shibahara, T., Ogawa, S., and Maeda, H., 1999, Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br. J. Cancer 80: 1945–1954.

    Article  PubMed  CAS  Google Scholar 

  62. Tanaka, S., Akaike, T., Fang, J., Beppu, T., Ogawa, M., Tamura, F., Miyamoto, Y., and Maeda, H., 2002, Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour. Br. J. Cancer (in press).

    Google Scholar 

  63. Maeda, H., Sawa, T., and Konno, T., 2001, Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J. Controlled Release 74: 47–61.

    Article  CAS  Google Scholar 

  64. Maeda, H., 2002, Enhanced permeability and Retention (EPR) Effect: Basis for Drug Targeting to Tumor. In Biomedical Aspects of Drug Targeting (V. Muzykantov and V. Torchilin, eds.), Kluwer Academic Publishers, Dordrecht.

    Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology, Kumamoto University School of Medicine, Kumamoto, 860-0811, Japan

    Jun Fang, Tomohiro Sawa & Hiroshi Maeda

Authors
  1. Jun Fang
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  2. Tomohiro Sawa
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  3. Hiroshi Maeda
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Editors and Affiliations

  1. Kumamoto University School of Medicine, Kumamoto, Japan

    Hiroshi Maeda

  2. University of Nebraska Medical Center, Omaha, Nebraska

    Alexander Kabanov

  3. University of Tokyo, Tokyo, Japan

    Kazunori Kataoka

  4. Tokyo Women’s Medical College, Tokyo, Japan

    Teruo Okano

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© 2004 Kluwer Academic Publishers

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Fang, J., Sawa, T., Maeda, H. (2004). Factors and Mechanism of “EPR” Effect and the Enhanced Antitumor Effects of Macromolecular Drugs Including SMANCS. In: Maeda, H., Kabanov, A., Kataoka, K., Okano, T. (eds) Polymer Drugs in the Clinical Stage. Advances in Experimental Medicine and Biology, vol 519. Springer, Boston, MA. https://doi.org/10.1007/0-306-47932-X_2

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  • DOI: https://doi.org/10.1007/0-306-47932-X_2

  • Publisher Name: Springer, Boston, MA

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