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

  • Jun Fang
  • Tomohiro Sawa
  • Hiroshi Maeda

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References

  1. 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.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 3.
    Maeda, H., and Matsumura, Y., 1989, Tumoritropic and lymphotropic principles of macromolecular drugs. Crit. Rev. Ther. Drug Carrier Sys. 6: 193–210.Google Scholar
  4. 4.
    Maeda, H., 1991, SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv. Drug Deliv. Rev. 6:181–202.CrossRefGoogle Scholar
  5. 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. 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.CrossRefGoogle Scholar
  7. 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. 8.
    Muggia, F. M., 1999, Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin. Cancer Res. 5: 7–8.PubMedGoogle Scholar
  9. 9.
    Folkman, J., 1971, Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182–1186.PubMedCrossRefGoogle Scholar
  10. 10.
    Folkman, J., and Shing, Y., 1992, Angiogenesis, J. Biol. Chem. 267: 10931–10934.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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. 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.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 23.
    Suzuki, M., Takahashi, T., and Sato, T., 1987, Medial regression and its functional significance in tumor-supplying host arteries. Cancer 59: 444–450.PubMedGoogle Scholar
  24. 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. 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.CrossRefPubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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. 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. 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.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 35.
    Maeda, H., and Yamamoto, T., 1996, Pathogenic mechanisms induced by microbial proteases in microbial infections. Biol. Chem. Hoppe-Seyler. 377: 217–226.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 38.
    Maeda, H., Wu, J., Okamoto, T., Maruo, K., and Akaike, T., 1999, Kallikrein-kinin in infection and cancer. Immunopharmacology. 43: 115–128.CrossRefPubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.CrossRefPubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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. 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. 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. 56.
    Konno, T., 1992, Targeting chemotherapy for hepatoma: arterial administration of anticancer drugs dissolved in Lipiodol. Eur. J. Cancer 28: 403–409.CrossRefPubMedGoogle Scholar
  57. 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. 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.PubMedGoogle Scholar
  59. 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.PubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedGoogle Scholar
  62. 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. 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.CrossRefGoogle Scholar
  64. 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

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Jun Fang
    • 1
  • Tomohiro Sawa
    • 1
  • Hiroshi Maeda
    • 1
  1. 1.Department of MicrobiologyKumamoto University School of MedicineKumamotoJapan

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