Skip to main content

Advertisement

SpringerLink
Log in

Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Combretastatin can prevent the supply of nutrients to cancer cells by selectively interrupting tumor blood flow (TBF). Therefore, combretastatin may serve as a new anticancer drug that utilizes starvation tactics to attack solid tumors. Among combretastatin compounds, combretastatin A-4 and a combretastatin A-4 derivative (Cderiv) are now in phase III clinical trials. These two combretastatin compounds have similar chemical structures and provide marked TBF interruption. However, their mechanisms of action are reportedly quite different and remain controversial. Precise mechanisms of action of these agents must be elucidated so as to develop safe clinical treatments and wider clinical applications. By using various kinds of rodent tumors, we showed that Cderiv produced potent interruption of TBF in all primary tumors and metastatic foci, without exception, and had beneficial therapeutic effects including significantly improved survival. Cderiv caused host arterioles to constrict. However, a tumor vascular bed scarcely reacted to a direct topical application of Cderiv. In addition, the fact that Cderiv did not have cytotoxic drug-like accumulated toxicity usually caused by repeated administration means that inhibition of tubulin polymerization by Cderiv may not occur to a great degree in vivo. Therefore, at least for Cderiv, our studies demonstrated that TBF interruption was mainly caused indirectly, via enhancement of vascular resistance of host arterioles, rather than being caused by a direct effect of Cderiv on tumor vessels. In this review, I describe cancer therapy that utilizes such TBF interruption, which leads to Cderiv-induced necrosis, and discuss details of its microcirculation mechanism.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Schlaeppi, J. M., & Wood, J. M. (1999). Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine-kinase inhibitors. Cancer and Metastasis Review, 18, 473–481.

    Article  CAS  Google Scholar 

  2. Folkman, J. (2003). Angiogenesis inhibitors: a new class of drugs. Cancer Biology & Therapy, 2, S127–S133.

    CAS  Google Scholar 

  3. Abdollahi, A., & Folkman, J. (2010). Evading tumor evasion: Current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resistance Updates, 13, 16–28.

    Article  PubMed  CAS  Google Scholar 

  4. Korpanty, G., Smyth, E., & Carney, D. N. (2011). Update on anti-angiogenic therapy in non-small cell lung cancer: Are we making progress? Journal of Thoracic Disease, 3, 19–29.

    PubMed  CAS  Google Scholar 

  5. Tozer, G. M., Kanthou, C., & Baguley, B. C. (2005). Disrupting tumour blood vessels. Nature Reviews. Cancer, 5, 423–435.

    Article  PubMed  CAS  Google Scholar 

  6. Hori, K. (2005). Cancer therapy by means of irreversible tumor blood flow stasis: Starvation tactics against solid tumors. Gene Therapy and Molecular Biology, 9, 203–216.

    Google Scholar 

  7. Kanthou, C., & Tozer, G. M. (2009). Microtubule depolymerizing vascular disrupting agents: Novel therapeutic agents for oncology and other pathologies. International Journal of Experimental Pathology, 90, 284–294.

    Article  PubMed  CAS  Google Scholar 

  8. McKeage, M. J., & Baguley, B. C. (2010). Disrupting established tumor blood vessels: An emerging therapeutic strategy for cancer. Cancer, 116, 1859–1871.

    Article  PubMed  CAS  Google Scholar 

  9. Siemann, D. W. (2011). The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treatment Reviews, 37, 63–74.

    Article  PubMed  CAS  Google Scholar 

  10. Folkman, J. (1971). Tumor angiogenesis: Therapeutic implications. New England Journal of Medicine, 285, 1182–1186.

    Article  PubMed  CAS  Google Scholar 

  11. Ferrara, N. (2002). VEGF and the quest for tumour angiogenesis factors. Nature Review Cancer, 2, 795–803.

    Article  CAS  Google Scholar 

  12. Ferrara, N., & Kerbel, R. S. (2005). Angiogenesis as a therapeutic target. Nature, 438, 967–974.

    Article  PubMed  CAS  Google Scholar 

  13. Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., et al. (2004). Direct evidence that the VEGF specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Medicine, 10, 145–147.

    Article  PubMed  CAS  Google Scholar 

  14. Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468, 824–828.

    Article  PubMed  CAS  Google Scholar 

  15. Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K. E., Geber, A., et al. (2010). Glioblastoma stem-like cells give rise to tumour endothelium. Nature, 468, 829–833.

    Article  PubMed  CAS  Google Scholar 

  16. Soda, Y., Marumoto, T., Friedmann-Morvinski, D., Soda, M., Liu, F., Michiue, H., et al. (2011). Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 108, 4274–4280.

    Article  PubMed  CAS  Google Scholar 

  17. Warren, B. A., & Shubik, P. (1966). The growth of the blood supply to melanoma transplants in the hamster cheek pouch. Laboratory Investigation, 15, 464–478.

    PubMed  CAS  Google Scholar 

  18. Hammersen, F., Endrich, B., & Messmer, K. (1985). The fine structure of tumor blood vessels. I. participation of non-endothelial cells in tumor angiogenesis. International Journal of Microcirculation Clinical and Experimental, 4, 31–43.

    CAS  Google Scholar 

  19. Maniotis, A. J., Folberg, R., Hess, A., Seftor, E. A., Gardner, L. M., Pe’er, J., et al. (1999). Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. American Journal of Pathology, 155, 739–752.

    Article  PubMed  CAS  Google Scholar 

  20. Carmeliet, P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature, 473, 298–307.

    Article  PubMed  CAS  Google Scholar 

  21. Ohsumi, K., Hatanaka, T., Fujita, K., Nakagawa, R., Fukuda, Y., Nihei, Y., et al. (1998). Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues. Bioorganic & Medical Chemistry Letters, 8, 3153–3158.

    Google Scholar 

  22. Goldstein, H. M., Wallace, S., Anderson, J. H., Bree, R. L., & Gianturco, C. (1976). Transcatheter occlusion of abdominal tumors. Radiology, 120, 539–545.

    PubMed  CAS  Google Scholar 

  23. Chung, V. P., & Wallace, S. (1981). Hepatic artery embolization in the treatment of hepatic neoplasms. Radiology, 140, 51–58.

    Google Scholar 

  24. Denekamp, J., Hill, S. A., & Hobson, B. (1983). Vascular occlusion and tumour cell death. European Journal of Cancer & Clinical Oncology, 19, 271–275.

    Article  CAS  Google Scholar 

  25. Kelly, M. G., & Hartwell, J. L. (1954). The biological effects and the chemical composition of podophyllin: A review. Journal of the National Cancer Institute, 14, 967–1010.

    PubMed  CAS  Google Scholar 

  26. Sackett, D. L. (1993). Podophyllotoxin, steganacin and combretastatin: Natural products that bind at the colchicine site of tubulin. Pharmacology & Therapeutics, 59, 163–228.

    Article  CAS  Google Scholar 

  27. Algire, G. H., Legallais, F. Y., & Anderson, B. F. (1954). Vascular reactions of normal and malignant tissues in vivo. VI. The role of hypotension in the action of components of podophyllin on transplanted sarcomas. Journal of the National Cancer Institute, 14, 879–893.

    PubMed  CAS  Google Scholar 

  28. Yue, Q.-X., Liu, X., & Guo, D.-A. (2010). Microtubule-binding natural products for cancer therapy. Planta Medica, 76, 1037–1043.

    Article  PubMed  CAS  Google Scholar 

  29. Hill, S. A., Lonergan, S. J., Denekamp, J., & Chaplin, D. J. (1993). Vinca alkaloids: anti-vascular effects in a murine tumour. European Journal of Cancer, 29, 1320–1324.

    Article  Google Scholar 

  30. Pettit, G. R., Cragg, G. M., Herald, D. L., Schmidt, J. M., & Lohavanijaya, P. (1982). Isolation and structure of combretastatin. Canadian Journal of Chemistry, 60, 1374–1376.

    Article  CAS  Google Scholar 

  31. Pettit, G. R., Singh, S. B., Hamel, E., Lin, C. M., Alberts, D. S., & Garcia-Kendall, D. (1989). Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia, 15, 209–211.

    Article  Google Scholar 

  32. Lin, C. M., Ho, H. H., Pettit, G. R., & Hamel, E. (1989). Antimitotic natural products combretastatin A-4 and combretastatin A-2: Studies on the mechanism of their inhibition of the binding of colchicine to tubulin. Biochemistry, 28, 6984–6991.

    Article  PubMed  CAS  Google Scholar 

  33. Dark, G. G., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit, G. R., & Chaplin, D. J. (1997). Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Research, 57, 1829–1834.

    PubMed  CAS  Google Scholar 

  34. Nam, N. H. (2003). Combretastatin A-4 analogues as antimitotic antitumor agents. Current Medicinal Chemistry, 10, 1697–1722.

    Article  PubMed  CAS  Google Scholar 

  35. Monk, K. A., Siles, R., Hadimani, M. B., Mugabe, B. E., Ackley, J. F., Studerus, S. W., et al. (2006). Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents. Bioorganic & Medicinal Chemistry, 14, 3231–3244.

    Article  CAS  Google Scholar 

  36. Dupeyre, G., Chabot, G. G., Thoret, S., Cachet, X., Seguin, J., Guénard, D., et al. (2006). Synthesis and biological evaluation of (3,4,5-trimethoxyphenyl)indol-3-ylmethane derivatives as potential antivascular agents. Bioorganic & Medicinal Chemistry, 14, 4410–4426.

    Article  CAS  Google Scholar 

  37. Hori, K. (2010). Cancer relapse prevention by means of tumor blood flow interruption after radiotherapy. Hoshasen Seibutsu Kenkyu, 45, 213–227.

    Google Scholar 

  38. Nihei, Y., Suga, Y., Morinaga, Y., Ohishi, K., Okano, A., Ohsumi, K., et al. (1999). A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors. Japanese Journal of Cancer Research, 90, 1016–1025.

    Article  PubMed  CAS  Google Scholar 

  39. Hori, K., Saito, S., Nihei, Y., Suzuki, M., & Sato, Y. (1999). Antitumor effects due to irreversible stoppage of tumor tissue blood flow: Evaluation of a novel combretastatin A-4 derivative, AC7700. Japanese Journal of Cancer Research, 90, 1026–1038.

    Article  PubMed  CAS  Google Scholar 

  40. Nihei, Y., Suzuki, M., Okano, A., Tsuji, T., Akiyama, Y., Tsuruo, T., et al. (1999). Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy. Japanese Journal of Cancer Research, 90, 1387–1395.

    Article  PubMed  CAS  Google Scholar 

  41. Hori, K., Saito, S., Sato, Y., & Kubota, K. (2001). Stoppage of blood flow in 3-methylcholanthrene-induced autochthonous primary tumor due to a novel combretastatin A-4 derivative, AC7700, and its antitumor effect. Medical Science Monitor, 7, 26–33.

    PubMed  CAS  Google Scholar 

  42. Hori, K., Saito, S., & Kubota, K. (2002). A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs. British Journal of Cancer, 86, 1604–1614.

    Article  PubMed  CAS  Google Scholar 

  43. Hori, K., Saito, S., Sato, Y., Akita, H., Kawaguchi, T., Sugiyama, K., et al. (2003). Differential relationship between changes in tumour size and microcirculatory functions induced by therapy with an antivascular drug and with cytotoxic drugs: implications for evaluation of therapeutic efficacy of AC7700 (AVE8062). European Journal of Cancer, 39, 1957–1966.

    Article  PubMed  CAS  Google Scholar 

  44. Hori, K., & Saito, S. (2003). Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumor blood flow stanching. British Journal of Cancer, 89, 1334–1344.

    Article  PubMed  CAS  Google Scholar 

  45. Hori, K., & Saito, S. (2004). Induction of tumour blood flow stasis and necrosis: A new function for epinephrine similar to that of combretastatin A-4 derivative AVE8062 (AC7700). British Journal of Cancer, 90, 549–553.

    Article  PubMed  CAS  Google Scholar 

  46. Ohno, T., Kawano, K., Sasaki, A., Aramaki, M., Tahara, K., Etoh, T., et al. (2002). Antitumor and antivascular effects of AC-7700, a combretastatin A-4 derivative, against rat liver cancer. International Journal of Clinical Oncology, 7, 171–176.

    Article  PubMed  CAS  Google Scholar 

  47. Tozer, G. M., Prise, V. E., Wilson, J., Cemazar, M., Shan, S., Dewhirst, M. W., et al. (2001). Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: Intravital microscopy and measurement of vascular permeability. Cancer Research, 61, 6413–6422.

    PubMed  CAS  Google Scholar 

  48. Eikesdal, H. P., Landuyt, W., & Dahl, O. (2002). The influence of combretastatin A-4 and vinblastine on interstitial fluid pressure in BT4An rat gliomas. Cancer Letters, 178, 209–217.

    Article  PubMed  CAS  Google Scholar 

  49. Ley, C. D., Horsman, M. R., & Kristjansen, P. E. (2007). Early effects of combretastatin-A4 disodium phosphate on tumor perfusion and interstitial fluid pressure. Neoplasia, 9, 108–112.

    Article  PubMed  CAS  Google Scholar 

  50. Kanthou, C., & Tozer, G. M. (2002). The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells. Blood, 99, 2060–2069.

    Article  PubMed  CAS  Google Scholar 

  51. Nallamothu, R., Wood, G. C., Kiani, M. F., Moore, B. M., Horton, F. P., & Thoma, L. A. (2006). A targeted liposome delivery system for combretastatin A4: Formulation optimization through drug loading and in vitro release studies. PDA Journal of Pharmaceutical Science and Technology, 60, 144–155.

    PubMed  CAS  Google Scholar 

  52. Wang, Y., Yang, T., Wang, X., Wang, J., Zhang, X., & Zhang, Q. (2010). Targeted polymeric micelle system for delivery of combretastatin A4 to tumor vasculature in vitro. Pharmaceutical Research, 27, 1861–1868.

    Article  PubMed  CAS  Google Scholar 

  53. Hori, K., Zhang, Q.-H., Saito, S., Tanda, S., Li, H.-C., & Suzuki, M. (1993). Microvascular mechanisms of change in tumor blood flow due to angiotensin II, epinephrine, and methoxamine: A functional morphometric study. Cancer Research, 53, 5528–5534.

    PubMed  CAS  Google Scholar 

  54. Hori, K., Suzuki, M., Tanda, S., & Saito, S. (1990). In vivo analysis of tumor vascularization in the rat. Japanese Journal of Cancer Research, 81, 279–288.

    Article  PubMed  CAS  Google Scholar 

  55. Nicoll, P. A., & Webb, R. L. (1946). Blood circulation in the subcutaneous tissue of the living bat’s wing. Annals of the New York Academy of Sciences, 46, 697–711.

    Article  Google Scholar 

  56. Lutz, B. R., & Fulton, G. P. (1954). The use of the hamster cheek pouch for the study of vascular changes at the microscopic level. The Anatomical Record, 120, 293–307.

    Article  PubMed  CAS  Google Scholar 

  57. Strahler, A. N. (1957). Quantitative analysis of watershed geomorphology. Transactions American Geophysical Union, 38, 913–920.

    Google Scholar 

  58. Kruuv, J. A., Inch, W. R., & McCredie, J. A. (1967). Blood flow and oxygenation of tumors in mice. II. Effects of vasodilator drugs. Cancer, 20, 60–65.

    Article  PubMed  CAS  Google Scholar 

  59. Suzuki, M., Hori, K., Abe, I., Saito, S., & Sato, H. (1984). Functional characterization of the microcirculation in tumors. Cancer Metastasis Review, 3, 115–126.

    Article  CAS  Google Scholar 

  60. Jirtle, R. L. (1988). Chemical modification of tumour blood flow. International Journal of Hyperthermia, 4, 355–371.

    Article  PubMed  CAS  Google Scholar 

  61. Hori, K., & Suzuki, M. (1992). Metastasis and vascularization. Mebio, 9, 50–56.

    Google Scholar 

  62. Hori, K., Suzuki, M., Tanda, S., & Saito, S. (1991). Characterization of heterogeneous distribution of tumor blood flow in the rat. Japanese Journal of Cancer Research, 82, 109–117.

    Article  PubMed  CAS  Google Scholar 

  63. Suzuki, M., Hori, K., Abe, I., Saito, S., & Sato, H. (1981). A new approach to cancer chemotherapy: Selective enhancement of tumor blood flow with angiotensin II. Journal of the National Cancer Institute, 67, 663–669.

    PubMed  CAS  Google Scholar 

  64. Hori, K. (2003). Cancer therapy due to irreversible tumor blood flow stanching: A novel therapeutic strategy for refractory cancers. Kareiigaku Kenkyusho Zasshi, 53, 1–19.

    Google Scholar 

Download references

Acknowledgments

I am grateful to Dr. Sachiko Saito for helpful suggestions and to Ms. Hiroko Oikawa for assistance with experiments. This study was supported by Grant-in-Aid for Cancer Research (12-Designated Research-1) from the Ministry of Health, Labor and Welfare, Japan; by Grant-in-Aid (No. 13218010; No. 14030005; No. 17591242) for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan; and by the Haruo Sato Fund for Yoshida Sarcoma and Ascites Hepatoma Memorial.

Conflicts of interest

I declare that I have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Vascular Biology, Division of Cancer Control, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai, 980-8575, Japan

    Katsuyoshi Hori

Authors
  1. Katsuyoshi Hori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katsuyoshi Hori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hori, K. Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism. Cancer Metastasis Rev 31, 109–122 (2012). https://doi.org/10.1007/s10555-011-9333-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-011-9333-9

Keywords

Search

Navigation