Varied Response of Spontaneous Tumors to Antiangiogenic Agents

  • Bruce M. Fenton
  • Scott F. Paoni
  • Brian Grimwood
  • Ivan Ding
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 566)


Since conventional therapies are directly dependent on the supply of either drugs or oxygen, a key question is whether antiangiogenic agents produce detrimental effects on tumor vascular function, thus compromising combination therapies. A second question is whether experimental results based on fast-growing, transplanted tumors mimic those in slowly developing spontaneous tumors, which may be more representative of response in human primary tumors. To investigate changes in tumor pathophysiology, three antiangiogenic agents were compared: a) endostatin, b) anti-VEGFR-2 (DC101), and c) celecoxib. Total blood vessels were identified using anti-CD31, perfused vessels using DiOC7, and hypoxia by EF5 uptake. Although individual tumor growth rates varied substantially, DC101 produced the most striking inhibition. DC101 increased total and perfused vessel spacing as well as overall hypoxia, while endostatin increased total vessel spacing, and hypoxia and celecoxib had no marked effects. These results reinforce the idea that pathophysiological changes in spontaneous tumors are in general reflective of response in transplanted tumors. Furthermore, although DC101 inhibited growth in roughly half of the spontaneous tumors, the remaining tumors were unaffected. A key focus of future studies will be to investigate the underlying rationale for the widely varying antiangiogenic response among tumors that outwardly appear so similar.


Tumor Hypoxia Antiangiogenic Agent Spontaneous Tumor Untreated Tumor Tumor Oxygenation 
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  1. 1.
    P. A. Burke, and S. J. DeNardo, Antiangiogenic agents and their promising potential in combined therapy, Crit. Rev. Oncol. Hematol. 39, 155–171 (2001).PubMedGoogle Scholar
  2. 2.
    J. C. Lee, D. C. Kim, M. S. Gee, H. M. Saunders, C. M. Sehgal, M. D. Feldman, S. R. Ross, and W. M. Lee, Interleukin-12 inhibits angiogenesis and growth of transplanted but not in situ mouse mammary tumor virus-induced mammary carcinomas, Cancer Res. 62, 747–755 (2002).PubMedGoogle Scholar
  3. 3.
    B. M. Fenton, S. F. Paoni, B. K. Beauchamp, B. Tran, L. Liang, B. Grimwood, and I. Ding, Evaluation of microregional variations in tumor hypoxia following the administration of endostatin, Adv. Exp. Med. Biol. 510, 19–24 (2003).PubMedGoogle Scholar
  4. 4.
    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).PubMedCrossRefGoogle Scholar
  5. 5.
    C. J. Bruns, M. Shrader, M. T. Harbison, C. Portera, C. C. Solorzano, K. W. Jauch, D. J. Hicklin, R. Radinsky, and L. M. Ellis, Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice, Int. J. Cancer 102, 101–108 (2002).PubMedCrossRefGoogle Scholar
  6. 6.
    Y. Izumi, E. di Tomaso, A. Hooper, P. Huang, J. Huber, D. J. Hicklin, D. Fukumura, R. K. Jain, and H. D. Suit, Responses to antiangiogenesis treatment of spontaneous autochthonous tumors and their isografts, Cancer Res. 63, 747–751 (2003).PubMedGoogle Scholar
  7. 7.
    K. M. Leahy, R. L. Ornberg, Y. Wang, B. S. Zweifel, A. T. Koki, and J. L. Masferrer, Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo, Cancer Res. 62, 625–631 (2002).PubMedGoogle Scholar
  8. 8.
    P. K. Lala, N. Al-Mutter, and A. Orucevic, Effects of chronic indomethacin therapy on the development and progression of spontaneous mammary tumors in C3H/HeJ mice, Int. J. Cancer 73, 371–380 (1997).PubMedCrossRefGoogle Scholar
  9. 9.
    B. M. Fenton, S. F. Paoni, J. Lee, C. J. Koch, and E. M. Lord, Quantification of tumor vascular development and hypoxia by immunohistochemical staining and HbO2 saturation measurements, Br. J. Cancer 79, 464–471 (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    E. M. Lord, L. Harwell, and C. J. Koch, Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts, Cancer Res. 53, 5721–5726 (1993).PubMedGoogle Scholar
  11. 11.
    B. M. Fenton, S. F. Paoni, B. K. Beauchamp, and I. Ding, Zonal image analysis of tumour vascular perfusion, hypoxia, and necrosis, Br. J. Cancer 86, 1831–1836 (2002).PubMedCrossRefGoogle Scholar
  12. 12.
    Y. Yokoyama, J. E. Green, V. P. Sukhatme, and S. Ramakrishnan, Effect of endostatin on spontaneous tumorigenesis of mammary adenocarcinomas in a transgenic mouse model, Cancer Res. 60, 4362–4365 (2000).PubMedGoogle Scholar
  13. 13.
    K. Boggio, E. Di Carlo, S. Rovero, F. Cavallo, E. Quaglino, P. L. Lollini, P. Nanni, G. Nicoletti, S. Wolf, P. Musiani, and G. Forni, Ability of systemic interleukin-12 to hamper progressive stages of mammary carcinogenesis in HER2/neu transgenic mice, Cancer Res. 60, 359–364 (2000).PubMedGoogle Scholar
  14. 14.
    G. Bergers, S. Song, N. Meyer-Morse, E. Bergsland, and D. Hanahan, Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors, J. Clin. Invest. 111, 1287–1295 (2003).PubMedCrossRefGoogle Scholar
  15. 15.
    G. Bergers, K. Javaherian, K. M. Lo, J. Folkman, and D. Hanahan, Effects of angiogenesis inhibitors on multistage carcinogenesis in mice, Science 284, 808–812 (1999).PubMedCrossRefGoogle Scholar
  16. 16.
    D. R. Sorensen, T. A. Read, T. Porwol, B. R. Olsen, R. Timpl, T. Sasaki, P. O. Iversen, H. B. Benestad, B. K. Sim, and R. Bjerkvig, Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma, Neuro-oncol 4, 1–8 (2002).PubMedCrossRefGoogle Scholar
  17. 17.
    B. M. Fenton, S. F. Paoni, B. G. Grimwood, and I. Ding, Disparate effects of endostatin on tumor vascular perfusion and hypoxia in two murine mammary carcinomas, Int. J. Radial. Oncol. Biol. Phys. 57(4), 1038–1046 (2003).CrossRefGoogle Scholar
  18. 18.
    N. N. Hanna, S. Seetharam, H. J. Mauceri, M. A. Beckett, N. T. Jaskowiak, R. M. Salloum, D. Hari, M. Dhanabal, R. Ramchandran, R. Kalluri, V. P. Sukhatme, D. W. Kufe, and R. R. Weichselbaum, Antitumor interaction of short-course endostatin and ionizing radiation, Cancer J. 6, 287–293 (2000).PubMedGoogle Scholar
  19. 19.
    M. Prewett, J. Huber, Y. W. Li, A. Santiago, W. O’Connor, K. King, J. Overholser, A. Hooper, B. Pytowski, L. Witte, P. Bohlen, and D. J. Hicklin, Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors, Cancer Res. 59, 5209–5218 (1999).PubMedGoogle Scholar
  20. 20.
    N. Hansen-Algenstaedt, B. R. Stall, T. P. Padera, D. E. J. G. Dolmans, D. J. Hicklin, D. Fukumura, and R. K. Jain, Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy, Cancer Res. 60, 4556–4560 (2000).PubMedGoogle Scholar
  21. 21.
    S. V. Kozin, Y. Boucher, D. J. Hicklin, P. Bohlen, R. K. Jain, and H. D. Suit, Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts, Cancer Res. 61, 39–44 (2001).PubMedGoogle Scholar
  22. 22.
    B. M. Fenton, B. K. Beauchamp, S. F. Paoni, P. Okunieff, and I. Ding, Characterization of the effects of antiangiogenic agents on tumor pathophysiology, Am. J. Clin. Oncol. 24, 453–457 (2001).PubMedCrossRefGoogle Scholar
  23. 23.
    J. L. Masferrer, K. M. Leahy, A. T. Koki, B. S. Zweifel, S. L. Settle, B. M. Woerner, D. A. Edwards, A. G. Flickinger, R. J. Moore, and K. Seibert, Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors, Cancer Res. 60, 1306–1311 (2000).PubMedGoogle Scholar
  24. 24.
    W. Shi, C. Teschendorf, N. Muzyczka, and D. W. Siemann, Gene therapy delivery of endostatin enhances the treatment efficacy of radiation, Radiother. Oncol. 66, 1–9 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Bruce M. Fenton
  • Scott F. Paoni
  • Brian Grimwood
  • Ivan Ding

There are no affiliations available

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