Skip to main content
Log in

Tumor Vasculature Directed Drug Targeting: Applying New Technologies and Knowledge to the Development of Clinically Relevant Therapies

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Recognition of the dependence of solid tumor growth on the formation of new blood vessels has ignited an enormous research effort aimed at the development of new therapeutic strategies for cancer. Besides direct application of drugs inhibiting endothelial cell function during angiogenesis, tumor vasculature directed drug-targeting strategies have been investigated for this purpose. In animal models of disease, proof of principle regarding the potential of selective interference with tumor blood flow as a powerful tumor therapy has been generated to its full extent. The challenge for the coming years will be to develop these strategies into clinically applicable ones. New insights into the molecular mechanisms prevailing in the endothelium during angiogenesis and into the mechanism(s) of action of drugs with anti-angiogenic activities, as well as new techniques to identify useful tumor endothelium specific target epitopes have in recent years been exploited to meet this challenge. This review summarizes vasculature directed therapeutic strategies proven to be successful in pre-clinical models and new (drug targeting) technologies enabling the development of more effective therapeutics for the treatment of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

REFERENCES

  1. M. S. O'Reilly, L. Holmgren, Y. Shing et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315–328 (1994).

    Google Scholar 

  2. X. Huang, G. Molema, S. King, L. Watkins, T. S. Edgington, and P. E. Thorpe. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275: 547–550 (1997).

    Google Scholar 

  3. G. Mavria and C. D. Porter. Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment. Gene Ther. 8:913–920 (2001).

    Google Scholar 

  4. H.-L. Kong and R. G. Crystal. Gene therapy strategies for tumor antiangiogenesis. J. Natl. Cancer Inst. 90:273–286 (1998).

    Google Scholar 

  5. A. W. Griffioen and G. Molema. Angiogenesis: potentials for pharmacological intervention in the treatment of cancer, cardiovascular diseases and chronic inflammation. Pharmacol. Rev. 52:237–268 (2000).

    Google Scholar 

  6. M. Everts, A. J. Schraa, L. F. M. H. de Leij, D. K. F. Meijer, and G. Molema. Vascular endothelium in inflamed tissue as a target for site selective delivery of drugs. In G. Molema and D. K. F. Meijer (eds.), Drug Targeting-Organ Specific Strategies, Wiley-VCH, Weinheim, New York, 2001 pp. 171–197

    Google Scholar 

  7. H. H. Sedlacek. Pharmacological aspects of targeting cancer gene therapy to endothelial cells. Crit. Rev. Oncol. Hematol. 37:169–215 (2001).

    Google Scholar 

  8. A. J. Schraa, M. Everts, R. J. Kok, S. A. Asgeirsdottir, and G. Molema. Selective targeting of pharmacologically active agents (in)to vascular endothelium for the treatment of cancer and chronic inflammatory diseases. In E. El-Gawely (ed.), Biotechnology Annual Review 8, 2002 pp. 133–165.

  9. R. K. Jain. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat. Med. 7:987–989 (2001).

    Google Scholar 

  10. D. H. Gorski, H. J. Mauceri, R. M. Salloum, et al. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res. 58:5686–5689 (1998).

    Google Scholar 

  11. A. Matter. Tumor angiogenesis as a therapeutic target. Drug Discov. Today 6:1005–1024 (2001).

    Google Scholar 

  12. M. S. O'Reilly, L. Holmgren, C. Chen, and J. Folkman. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Med. 2:689–692 (1996).

    Google Scholar 

  13. T. Boehm, J. Folkman, T. Browder, and M. S. O'Reilly. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407 (1997).

    Google Scholar 

  14. M. Guba, P. von Breitenbuch, M. Steinbauer, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med. 8:128–135 (2002).

    Google Scholar 

  15. R. Baluna, J. Rizo, B. E. Gordon, V. Ghetie, and E. S. Vitetta. Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc. Natl. Acad. Sci. USA 96:3957–3962 (1999).

    Google Scholar 

  16. M. R. McDevitt, D. Ma, L. T. Lai, et al. Tumor therapy with targeted atomic nanogenerators. Science 294:1537–1540 (2001).

    Google Scholar 

  17. J. C. Reed. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol. Med. 7:314–319 (2001).

    Google Scholar 

  18. D. W. J. van der Schaft, S. Ramakrishnan, G. Molema, and A. W. Griffioen., In G. Molema and D. K. F. Meijer (eds.), Tumor vasculature targeting. Drug targeting-Organ-Specific Strategies, Wiley-VCH, Weinheim, New York, 2001 pp. 233–254.

    Google Scholar 

  19. D. Bouis, G. Hospers, C. Meijer, G. Molema, and N. Mulder. Endothelium in vitro: a review of human vascular endothelial cell lines for blood vessel-related research. Angiogenesis 4:102 (2001).

    Google Scholar 

  20. B. Bartling, H. Tostlebe, D. Darmer, J. Holtz, R. E. Silber, and H. Morawietz. Shear stress-dependent expression of apoptosisregulating genes in endothelial cells. Biochem. Biophys. Res. Commun. 278:740–746 (2000).

    Google Scholar 

  21. M. Bongrazio, C. Baumann, A. Zakrzewicz, A. R. Pries, and P. Gaehtgens. Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress. Cardiovasc. Res. 47:384–393 (2000).

    Google Scholar 

  22. R. Mutuberria, J. W. Arends, A. W. Griffioen, and H. R. Hoogenboom. Phage display technology for target discovery in drug delivery research. In G. Molema and Meijer D. K. F. (eds.), Drug targeting-organ specific strategies, Wiley-VCH, Weinheim, New York, 2001 pp. 255–273.

    Google Scholar 

  23. R. Pasqualini, E. Koivunen, and E. Ruoslahti. ?v integrins as receptors for tumor targeting by circulating ligands. Nature Biotech . 15:542–546 (1997).

    Google Scholar 

  24. R. J. Giordano, M. Cardo-Vila, J. Lahdenranta, R. Pasqualini, and W. Arap. Biopanning and rapid analysis of selective interactive ligands. Nat. Med. 7:1249–1253 (2001).

    Google Scholar 

  25. D. Rajotte, W. Arap, M. Hagedorn, E. Koivunen, R. Pasqualini, and E. Ruoslahti. Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display. J. Clin. Invest. 102:430–437 (1998).

    Google Scholar 

  26. U. B. Nielsen and J. D. Marks. Internalizing antibodies and targeted cancer therapy: direct selection from phage display libraries. PSTT 3:282–291 (2000).

    Google Scholar 

  27. W. Arap, M. G. Kolonin, M. Trepel, et al. Steps toward mapping the human vasculature by phage display. Nat. Med. 8:121–127 (2002).

    Google Scholar 

  28. B. S. Jacobson, J. E. Schnitzer, M. McCaffery, and G. E. Palade. Isolation and partial characterization of the luminal plasmalemma of microvascular endothelium from rat lungs. Eur. J. Cell. Biol. 58:296–306 (1992).

    Google Scholar 

  29. J. E. Schnitzer. Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo. Adv. Drug Deliv. Rev. 49:265–280 (2001).

    Google Scholar 

  30. B. St Croix, C. Rago, V. Velculescu, et al. Genes expressed in human tumor endothelium. Science 289:1197–1202 (2000).

    Google Scholar 

  31. E. B. Carson-Walter, D. N. Watkins, A. Nanda, B. Vogelstein, K. W. Kinzler, and B. St Croix. Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res. 61:6649–6655 (2001).

    Google Scholar 

  32. F. V. Peale, Jr. and M. E. Gerritsen. Gene profiling techniques and their application in angiogenesis and vascular development. J. Pathol. 195:7–19 (2001).

    Google Scholar 

  33. R. L. Strausberg, S. F. Greenhut, L. H. Grouse, C. F. Schaefer, and K. H. Buetow. In silico analysis of cancer through the Cancer Genome Anatomy Project. Trends Cell Biol. 11:S66–S71 (2001).

    Google Scholar 

  34. S. D. Jayasena. Aptamers: an emerging class of molecules that rival antibodies in diagnostics. Clin. Chem. 45:1628–1650 (1999).

    Google Scholar 

  35. M. C. Willis, B. D. Collins, T. Zhang, et al. Liposome-anchored vascular endothelial growth factor aptamers. Bioconjug. Chem. 9:573–582 (1998).

    Google Scholar 

  36. F. Yuan, M. Dellian, D. Fukumura, et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55:3752–3756 (1995).

    Google Scholar 

  37. S. A. Nicklin, D. J. Von Seggern, L. M. Work, et al. Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus. Mol. Ther. 4:534–542 (2001).

    Google Scholar 

  38. P. N. Reynolds, S. A. Nicklin, L. Kaliberova, et al. Combined transductional and transcriptional targeting improves the specificity of transgene expression in vivo. Nat. Biotechnol. 19:838–842 (2001).

    Google Scholar 

  39. C. J. Kuo, F. Farnebo, E. Y. Yu, et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc. Natl. Acad. Sci. USA 98:4605–4610 (2001).

    Google Scholar 

  40. O. Kisker, C. M. Becker, D. Prox, et al. Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res. 61:7669–7674 (2001).

    Google Scholar 

  41. J. O. Ojeifo, H. R. Lee, P. Rezza, N. Su, and J. A. Zwiebel. Endothelial cell-based systemic gene therapy of metastatic melanoma. Cancer Gene Ther. 8:636–648 (2001).

    Google Scholar 

  42. P. Benzinger, G. Martiny-Baron, P. Reusch, et al. Targeting of endothelial KDR receptors with 3G2 immunoliposomes in vitro. Biochim. Biophys. Acta. 1466:71–78 (2000).

    Google Scholar 

  43. K. Muller, T. Nahde, A. Fahr, R. Muller, and S. Brusselbach. Highly efficient transduction of endothelial cells by targeted artificial virus-like particles. Cancer Gene Ther. 8:107–117 (2001).

    Google Scholar 

  44. W. Arap, R. Pasqualini, and E. Ruoslahti. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279:377–380 (1998).

    Google Scholar 

  45. H. M. Ellerby, W. Arap, L. M. Ellerby, et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat. Med. 5:1032–1038 (1999).

    Google Scholar 

  46. C. D. Buckley, D. Pilling, N. V. Henriquez, et al. RGD peptides induce apoptosis by direct caspase-3 activation. Nature 397:534–539 (1999).

    Google Scholar 

  47. F. Curnis, A. Sacchi, L. Borgna, F. Magni, A. Gasparri, and A. Corti. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat. Biotechnol. 18:1185–1190 (2000).

    Google Scholar 

  48. R. J. Kok, A. J. Schraa, E. J. Bos, et al. Preparation and functional evaluation of RGD-modified proteins as alpha(v)beta(3) integrin directed therapeutics. Bioconjug. Chem. 13:128–135 (2002).

    Google Scholar 

  49. A. J. Schraa, R. J. Kok, H. E. Moorlag, et al. Pharmacokinetics and organ distribution of RGD-modified protein conjugates developed for tumor vasculature targeting. Submitted.

  50. T. A. Olson, D. Mohanraj, S. Roy, and S. Ramakrishnan. Targeting the tumor vasculature: inhibition of tumor growth by a vascular endothelial growth factor-toxin conjugate. Int. J. Cancer 73:865–870 (1997).

    Google Scholar 

  51. N. Arora, R. Masood, T. Zheng, J. Cai, D. L. Smith, and P. S. Gill. Vascular endothelial growth factor chimeric toxin is highly active against endothelial cells. Cancer Res. 59:183–188 (1999).

    Google Scholar 

  52. S. Ran, B. Gao, S. Duffy, L. Watkins, N. Rote, and P. E. Thorpe. Infarction of solid Hodgkin's tumors in mice by antibodydirected targeting of tissue factor to tumor vasculature. Cancer Res. 58:4646–4653 (1998).

    Google Scholar 

  53. F. Nilsson, H. Kosmehl, L. Zardi, and D. Neri. 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. 61:711–716 (2001).

    Google Scholar 

  54. A. Viloria-Petit, T. Crombet, S. Jothy, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 61:5090–5101 (2001).

    Google Scholar 

  55. Y. Maeshima, A. Sudhakar, J. C. Lively, et al. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science 295:140–143 (2002).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molema, G. Tumor Vasculature Directed Drug Targeting: Applying New Technologies and Knowledge to the Development of Clinically Relevant Therapies. Pharm Res 19, 1251–1258 (2002). https://doi.org/10.1023/A:1020312220968

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020312220968

Navigation