Ligand-Directed Destruction of Tumor Vasculature

  • Sophia Ran
  • Michael Rosenblum
  • Philip E. Thorpe
Chapter

Abstract

Vascular targeting agents (VTA) are designed to bind selectively to components of tumor vasculature and deliver an effector molecule that, directly or indirectly, causes occlusion of the tumor vessels. Blood flow to the tumor thus ceases, resulting in tumor cell death due to the cells’ inability to obtain oxygen and nutrients (Fig. 1, below). This approach has several advantages. Firstly, the tumor endothelial cells are directly accessible to intravenously administrated therapeutic agents, permitting rapid localization of a high percentage of the injected dose. Secondly, since each capillary provides oxygen and nutrients for thousands of tumor cells, occlusion of the vessel has an amplified effect on tumor cells. Thirdly, the outgrowth of mutant endothelial cells lacking the target antigen is unlikely because they comprise a normal, genetically stable cell population. Finally, since tumor vessels share common morphological and biochemical properties, this strategy should be applicable to different tumor types.

Keywords

Tissue Factor Vascular Endothelial Growth Factor Receptor Tumor Vasculature Tumor Vessel Tumor Endothelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Folkman, J. and Shing, Y. Angiogenesis. J.Biol.Chem., 267: 10931–10934, 1992.Google Scholar
  2. 2.
    Hillen, H. F. Thrombosis in cancer patients. Ann.of Oncol., 11 (SUPPL 3): 273–276, 2000.Google Scholar
  3. 3.
    Wilcox, J. N., Smith, K. M., Schwartz, S. M., and Gordon, D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc.Natl.Acad.Sci.USA, 86: 2839–2843, 1989.CrossRefGoogle Scholar
  4. 4.
    Ruf, W., Rehemtulla, A., and Edgington, T. S. Phospholipid-independent and–dependent interactions required for tissue factor receptor and cofactor function. J.Biol.Chem., 266: 2158–2166, 1991.Google Scholar
  5. 5.
    Huang, X., Molema, G., King, S., Watkins, L., Edgington, T. S., and Thorpe, P. E. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science, 275: 547–550, 1997.CrossRefGoogle Scholar
  6. 6.
    Ruco, L. P., Pomponi, D., Pigott, R., Stoppacciaro, A., Monardo, F., Uccini, S., Boaraschi, D., Tagliabue, A., Santoni, A., Dejana, E., Mantovani, A., and Baroni, C. D. Cytokine production (IL-a alpha, IL-1 beta, and TNF alpha) and endothelial cell activation (ELAM-1 and HLA-DR) in reactive lymphadenitis, hodgkin’s disease, and in non-hodgkin’s lymphomas. Am. J Pathol., 137(5): 1163–1171, 1990.Google Scholar
  7. 7.
    Ran, S., Gao, B., Duffy, S., Watkins, L., Rote, N. S., and Thorpe, P. E. Infarction of solid Hodgkin’s tumors in mice by antibody-directed targeting of tissue factor to tumor vasculature. Cancer Res, 58(20): 4646–4653, 1998.Google Scholar
  8. 8.
    Viti, F., Tarli, L., Giovannoni, L., Zardi, L., and Neri, D. Increased binding affinity and valence of recombinant antibody fragments lead to improved targeting of tumoral angiogenesis. Cancer Res, 59: 347–352, 1999.Google Scholar
  9. 9.
    Nilsson, F., Kosmehl, H., Zardi, L., and Neri, D. Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice. Cancer Res, 61(2): 711–716, 2001.Google Scholar
  10. 10.
    Williamson, P. and Schlegel, R. A. Back and forth: the regulation and function of transbilayer phospholipid movement in eukaryotic cells. Molec.Mem.Biol., 11: 199216, 1994.Google Scholar
  11. 11.
    Camemolla, B., Balza, E., Siri, A., Zardi, L., Nicotra, M. R., Bigotti, A., and Natali, P. G. A tumor-associated fibronectin isoform generated by alternative splicing of messenger RNA precursors. J.Cell Biol., 108: 1139–1148, 1989.CrossRefGoogle Scholar
  12. 12.
    Karelina, TV. and Eisen, A. Z. Interstitial collagenase and the ED-B oncofetal domain of fibronectin are markers of angiogenesis in human skin tumors. Cancer Detect.Prev., 22(5): 438–444, 1998.Google Scholar
  13. 13.
    Israeli, R. S., Powell, C. T., Fair, W. R., and Heston, W. D. W. Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res, 53: 227–230, 1993.Google Scholar
  14. 14.
    Silver, D. A., Pellicer, I., Fair, W. R., Heston, W. D. W., and Cordon-Cardo, C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin.Cancer Res., 3: 81–85, 1997.Google Scholar
  15. 15.
    Shweiki, D., Itin, A., Neufeld, G., Gitay-Goren, H., and Keshet, E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J.Clin.Invest., 91: 2235–2243, 1993.CrossRefGoogle Scholar
  16. 16.
    Dvorak, H. F., Sioussat, T. M., Brown, L. F., Berse, B., Nagy, J. A., Sotrel, A., Manseau, E. J., Vandewater, L., and Senger, D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors–concentration in tumor blood vessels. J.Exp.Med., 174: 1275–1278, 1991.CrossRefGoogle Scholar
  17. 17.
    Brekken, R. A., Overholser, J., Stastny, V. A., Waltenberger, J., Minna, J., and Thorpe, P. E. Selective inhibition of vascular endothelial growth factor (VEGF) receptor2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res, 60: 5117–5124, 2000.Google Scholar
  18. 18.
    Cooke, S. P., Boxer, G. M., Lawrence, L., Pedley, R. B., Spencer, D. I. R., Begent, R. H. J., and Chester, K. A. A strategy for antitumor vascular therapy by targeting the vascular endothelial growth factor:receptor complex. Cancer Res, 61: 3653–3659, 2001.Google Scholar
  19. 19.
    Ramakrishnan, S., Olson, T. A., Bautch, V. L., and Mohanraj, D. Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-l-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res., 56: 1324–1330, 1996.Google Scholar
  20. 20.
    Fonsatti, E., Del Vecchio, L., Altomonte, M., Sigalotti, L., Nicotra, M. R., Coral, S., Natali, P. G., and Maio, M. Endoglin: an accessory component of the TGF-E-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J.Cell.Physiol., 188: 1–7, 2001.CrossRefGoogle Scholar
  21. 21.
    Burrows, F. J., Derbyshire, E. J., Tazzari, P. L., Amlot, P., Gazdar, A. F., King, S. W., Letarte, M., Vitetta, E. S., and Thorpe, P. E. Endoglin is an endothelial cell proliferation marker that is upregulated in tumor vasculature. Clin.Cancer Res., 1: 1623–1634, 1995.Google Scholar
  22. 22.
    Seon, B. K., Matsuno, F., Haruta, Y., Kondo, M., and Barcos, M. Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. Clin.Cancer Res., 3: 1031–1044, 1997.Google Scholar
  23. 23.
    Rettig, W. J., Garinchesa, P., Healey, J. H., Su, S. L., Jaffe, E. A., and Old, L. J. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl.Acad.Sci.USA, 89: 10832–10836, 1992.CrossRefGoogle Scholar
  24. 24.
    Carson-Walter, E. B., Watkins, D. N., Nanda, A., Vogelstein, B., Kinzler, K. W., and St.Croix, B. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res, 61(18): 6649–6655, 2001.Google Scholar
  25. 25.
    Christian, S., Ahorn, H., Koehler, A., Eisenhaber, F., Rodi, H. P., Garin-Chesa, P., Park, J. E., Rettig, W. J., and Lenter, M. C. Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium. J Biol.Chem, 276(10): 7408–7414, 2001.Google Scholar
  26. 26.
    Brooks, P. C., Clark, R. A., and Cheresh, D. A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science, 264: 569–571, 1994.CrossRefGoogle Scholar
  27. 27.
    Brooks, P. C., Montgomery, A. M. P., Rosenfeld, M., Reisfeld, R. A., Hu, T., Klier, G., and Cheresh, D. A. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 79: 1157–1164, 1994.CrossRefGoogle Scholar
  28. 28.
    Pasqualini, R., Koivunen, E., and Ruoslahti, E. Alpha v integrins as receptors for tumor targeting by circulating ligands. Nature Biotechnology, 15(6): 542–546, 1997.Google Scholar
  29. 29.
    Lode, H. N., Moehler, T., Xiang, R., Jonczyk, A., Gillies, S. D., Cheresh, D. A., and Reisfeld, R. A. Synergy between an antiangiogenic integrin alpha V antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. Proc.Natl.Acad.Sci.(USA), 96(4): 1591–1596, 1999.Google Scholar
  30. 30.
    Arap, W., Pasqualini, R., and Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science, 279: 377–380, 1998.CrossRefGoogle Scholar
  31. 31.
    Ohizumi, I., Tsunoda, S., Taniguchi, K., Saito, H., Esaki, K., Koizumi, K., Makimoto, H., Wakai, Y., Matsui, J., Tsutsumi, Y., Nakagawa, S., Utoguchi, N., Ohsugi, Y., and Mayumi, T. Identification of tumor vascular antigens by monoclonal antibodies prepared from rat-tumor-derived endothelial cells. Int J Cancer, 77(4): 561–566, 1998.Google Scholar
  32. 32.
    Jacobson, B. S., Stolz, D. B., and Schnitzer, J. E. Identification of endothelial cell-surface proteins as targets for diagnosis and treatment of disease. Nature Med., 2: 482–484, 1996.CrossRefGoogle Scholar
  33. 33.
    St.Croix, B., Rago, C., Velculescu, V., Traverso, G., Romans, K. E., Montgomery, E., Lal, A., Riggins, G. J., Lengauer, C., Vogelstein, B., and Kinzler, K. W. Genes expressed in human tumor endothelium. Science, 289(5482): 1197–1202, 2000.Google Scholar
  34. 34.
    Pasqualini, R. and Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature, 380: 364–366, 1996.CrossRefGoogle Scholar
  35. 35.
    Ruoslahti, E. Targeting tumor vasculature with homing peptides from phage display. Semin Cancer Biol, 10(6): 435–442, 2000.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Sophia Ran
    • 1
  • Michael Rosenblum
    • 2
  • Philip E. Thorpe
    • 1
  1. 1.The University of Texas Southwestern Medical Center at DallasDallasUSA
  2. 2.M.D. Anderson Cancer CenterHoustonUSA

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