Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Disrupting tumour blood vessels

Nature Reviews Cancer volume 5, pages 423–435 (2005)Cite this article

Key Points

  • Solid tumours require a functional blood supply for their continued growth, and the established tumour vasculature is therefore an attractive target for therapy. Low-molecular-weight vascular-disrupting agents (VDAs) cause the rapid and selective shutdown of tumour blood flow.

  • The combretastatins and drugs related to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are the two main groups of VDAs that are currently in preclinical and clinical development.

  • In endothelial cells in culture, combretastatin A-4 3-O-phosphate (CA-4-P; the lead combretastatin) and DMXAA cause rapid re-organization of the actin cytoskeleton, mediated by disruption of the tubulin cytoskeleton for CA-4-P but not DMXAA.

  • An increase in vascular permeability is likely to be an important component of the mechanisms that lead to the shutdown of tumour blood flow by both classes of drug.

  • Signalling pathways associated with CA-4-P and their effects on permeability involve the small GTPase RHO and RHO kinase, as well as stress-activated protein kinase 2 (SAPK2).

  • The basis for the susceptibility of the tumour vasculature to the VDAs that are currently in preclinical and clinical development is unclear, although there is evidence that, across different tumour types, increased susceptibility correlates with increased permeability of tumour blood vessels.

  • Factors in the tumour microenvironment are likely to influence the susceptibility of tumour blood vessels to VDAs and this is currently under investigation.

  • Other low-molecular-weight VDAs currently under development include several other natural and synthetic combretastatins, other tubulin-binding agents and inhibitors of junctional proteins.

  • Phase I and II clinical trials have confirmed the tumour selectivity of CA-4-P and DMXAA in the clinical setting. The therapeutic potential of VDAs lies in their combination with conventional and/or other novel cancer treatments; such combinations are currently being tested in clinical trials involving radiotherapy, chemotherapy and radioimmunotherapy.

Abstract

Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) — one of a structurally distinct group of drugs — is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chemical structures of some vascular disrupting agents.
Figure 2: Disruption of endothelial cells by treatment with CA-4-P or DMXAA.
Figure 3: Proposed mechanisms for rapid tumour vascular shutdown after treatment with CA-4-P or DMXAA.
Figure 4: Disodium combretastatin A-4 3-O-phosphate (CA-4-P)-induced stimulation of endothelial-cell signalling pathways associated with elevated permeability.

Similar content being viewed by others

References

  1. Boyland, E. & Boyland, M. E. Studies in tissue metabolism. IX. The action of colchicine and B. typhosus extract. Biochem. J. 31, 454–460 (1937).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Seed, L., Slaughter, D. P. & Limarzi, L. R. Effect of colchicine on human carcinoma. Surgery 7, 696–709 (1940).

    Google Scholar 

  3. Ludford, R. J. Factors determining the action of colchicine on tumour growth. Br. J. Cancer 2, 75–86 (1948).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Algire, G. H., Legallais, F. Y. & Anderson, B. F. Vascular reactions of normal and malignant tissues in vivo. VI. The role of hypotension in the action of components of podophyllotoxin on transplanted sarcomas. J. Natl Cancer Inst. 14, 879–887 (1954). One of a classic series of papers on the vascular reactions of tumours.

    CAS  PubMed  Google Scholar 

  5. Baguley, B. C., Holdaway, K. M., Thomsen, L. L., Zhuang, L. & Zwi, L. J. Inhibition of growth of colon 38 adenocarcinoma by vinblastine and colchicine: evidence for a vascular mechanism. Eur. J. Cancer 27, 482–487 (1991).

    CAS  PubMed  Google Scholar 

  6. Hill, S. A., Lonergan, S. J., Denekamp, J. & Chaplin, D. J. Vinca alkaloids: anti-vascular effects in a murine tumour. Eur. J. Cancer 9, 1320–1324 (1993).

    Google Scholar 

  7. Hill, S. A., Sampson, L. E. & Chaplin, D. J. Anti-vascular approaches to solid tumour therapy: evaluation of vinblastine and flavone acetic acid. Int. J. Cancer 63, 119–123 (1995).

    CAS  PubMed  Google Scholar 

  8. Pettit, G. R., Cragg, G. M. & Singh, S. B. Antineoplastic agents, 122. Constituents of Combretum caffrum. J. Nat. Prod. 50, 386–391 (1987). Describes the isolation of the combretastatins from their natural source.

    CAS  PubMed  Google Scholar 

  9. Lin, C. M. et al. Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structural-activity study. Mol. Pharmacol. 34, 200–208 (1988).

    CAS  PubMed  Google Scholar 

  10. Pettit, G. R. et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des. 10, 299–309 (1995). Describes the synthesis of CA-4-P, the more soluble prodrug of CA-4, allowing its use in in vivo model systems.

    CAS  PubMed  Google Scholar 

  11. McGown, A. T. & Fox, B. W. Structural and biochemical comparison of the anti-mitotic agents colchicine, combretastatin A4 and amphethinile. Anticancer Drug Des. 3, 249–254 (1989).

    PubMed  Google Scholar 

  12. Pettit, G. R. & Lippert III, J. W. Antineoplastic agents 429. Syntheses of the combretastatin A-1 and combretastatin B-1 prodrugs. Anticancer Drug Des. 15, 203–216 (2000).

    CAS  PubMed  Google Scholar 

  13. Holwell, S. E. & Bibby, M. C. Activity of combretastatin A1 phosphate in murine models of liver metastasis. Br. J. Cancer 85 (Suppl. 1), 34 (2001).

    Google Scholar 

  14. Hill, S. A., Tozer, G. M. & Chaplin, D. J. Preclinical evaluation of the antitumour activity of the novel vascular targeting agent Oxi 4503. Anticancer Res. 22, 1453–1458 (2002).

    CAS  PubMed  Google Scholar 

  15. Holwell, S. E. et al. Combretastatin A-1 phosphate a novel tubulin-binding agent with in vivo vascular effects in experimental tumours. Anticancer Res. 22, 707–711 (2002).

    CAS  PubMed  Google Scholar 

  16. Hua, J. et al. Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate. Anticancer Res. 23, 1433–1440 (2003).

    CAS  PubMed  Google Scholar 

  17. Aleksandrzak, K., McGown, A. T. & Hadfield, J. A. Antimitotic activity of diaryl compounds with structures resembling combretastatin A-4. Anticancer Drugs 9, 545–550 (1998).

    CAS  PubMed  Google Scholar 

  18. Hatanaka, T. et al. Novel B-ring modified combretastatin analogues: syntheses and antineoplastic activity. Bioorg. Med. Chem. Lett. 8, 3371–3374 (1998).

    CAS  PubMed  Google Scholar 

  19. Ohsumi, K. et al. Novel combretastatin analogues effective against murine solid tumors: design and structure–activity relationships. J. Med. Chem. 41, 3022–3032 (1998).

    CAS  PubMed  Google Scholar 

  20. Pettit, G. R. et al. Antineoplastic agents. 379. Synthesis of phenstatin phosphate. J. Med. Chem. 41, 1688–1695 (1998).

    CAS  PubMed  Google Scholar 

  21. Lawrence, N. J., Rennison, D., Woo, M., McGown, A. T. & Hadfield, J. A. Antimitotic and cell growth inhibitory properties of combretastatin A-4-like ethers. Bioorg. Med. Chem. Lett. 11, 51–54 (2001).

    CAS  PubMed  Google Scholar 

  22. Hadimani, M. B. et al. Synthesis, in vitro, and in vivo evaluation of phosphate ester derivatives of combretastatin A-4. Bioorg. Med. Chem. Lett. 13, 1505–1508 (2003).

    CAS  PubMed  Google Scholar 

  23. Liou, J. P. et al. Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. J. Med. Chem. 47, 4247–4257 (2004).

    CAS  PubMed  Google Scholar 

  24. Perez-Melero, C. et al. A new family of quinoline and quinoxaline analogues of combretastatins. Bioorg. Med. Chem. Lett. 14, 3771–3774 (2004).

    CAS  PubMed  Google Scholar 

  25. Sun, L., Vasilevich, N. I., Fuselier, J. A., Hocart, S. J. & Coy, D. H. Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design. Bioorg. Med. Chem. Lett. 14, 2041–2046 (2004).

    CAS  PubMed  Google Scholar 

  26. Prinz, H. Recent advances in the field of tubulin polymerization inhibitors. Expert Rev. Anticancer Ther. 2, 695–708 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nihei, Y. et al. A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors. Jpn. J. Cancer Res. 90, 1016–1025 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Beauregard, D. A. et al. Magnetic resonance imaging and spectroscopy of combretastain A4 prodrug-induced disruption of tumour perfusion and energetic status. Br. J. Cancer 77, 1761–1767 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dark, G. D. et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 57, 1829–1834 (1997). The first solid evidence for the combretastatins having a potent and selective vascular-disrupting effect in solid tumours.

    CAS  PubMed  Google Scholar 

  33. Horsman, M., Ehrnrooth, E., Ladekarl, M. & Overgaard, J. The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors. Int. J. Radiat. Oncol. Biol. Phys. 42, 895–898 (1998).

    CAS  PubMed  Google Scholar 

  34. Maxwell, R. J., Nielsen, F. U., Breidahl, T., Stodkilde-Jorgensen, H. & Horsman, M. R. Effects of combretastatin on murine tumours monitored by 31P MRS, 1H MRS and 1H MRI. Int. J. Radiat. Oncol. Biol. Phys. 42, 891–894 (1998).

    CAS  PubMed  Google Scholar 

  35. Chaplin, D. J., Pettit, G. R. & Hill, S. A. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 19, 189–196 (1999).

    CAS  PubMed  Google Scholar 

  36. Grosios, K., Holwell, S. E., McGown, A. T., Pettit, G. R. & Bibby, M. C. In vivo and in vitro evaluation of combretastatin A-4 and its sodium phosphate prodrug. Br. J. Cancer 81, 1318–1327 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tozer, G. M. et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res. 59, 1626–1634 (1999).

    CAS  PubMed  Google Scholar 

  38. Pedley, R. B. et al. Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin a-4 3-O-phosphate. Cancer Res. 61, 4716–4722 (2001).

    CAS  PubMed  Google Scholar 

  39. Lin, C. M., Ho, H. H., Pettit, G. R. & Hamel, E. 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 (1989).

    CAS  PubMed  Google Scholar 

  40. Rustin, G. J. et al. Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results. J. Clin. Oncol. 21, 2815–2822 (2003).

    CAS  PubMed  Google Scholar 

  41. Plowman, J. et al. Flavone acetic acid: a novel agent with preclinical antitumor activity against colon adenocarcinoma 38 in mice. Cancer Treat. Rep. 70, 631–635 (1986).

    CAS  PubMed  Google Scholar 

  42. Smith, G. P., Calveley, S. B., Smith, M. J. & Baguley, B. C. Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumours. Eur. J. Cancer Clin. Oncol. 23, 1209–1211 (1987).

    CAS  PubMed  Google Scholar 

  43. Evelhoch, J. L. et al. Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy. Cancer Res. 48, 4749–4755 (1988).

    CAS  PubMed  Google Scholar 

  44. Hill, S. A., Williams, K. B. & Denekamp, J. Vascular collapse after flavone acetic acid: a possible mechanism of its anti-tumour action. Eur. J. Cancer Clin. Oncol. 25, 1419–1424 (1989).

    CAS  PubMed  Google Scholar 

  45. Zwi, L. J., Baguley, B. C., Gavin, J. B. & Wilson, W. R. Blood flow failure as a major determinant in the antitumor action of flavone acetic acid. J. Natl. Cancer Inst. 81, 1005–1013 (1989). References 44 and 45 provide an early introduction to the concept of vascular shutdown and how it might be measured.

    CAS  PubMed  Google Scholar 

  46. Denekamp, J., Hill, S. A. & Hobson, B. Vascular occlusion and tumour cell death. Eur. J. Cancer Clin. Oncl. 19, 271–275 (1983).

    CAS  Google Scholar 

  47. Baguley, B. C. Antivascular therapy of cancer: DMXAA. Lancet Oncol. 4, 141–148 (2003).

    CAS  PubMed  Google Scholar 

  48. Jameson, M. B. et al. Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent. Br. J. Cancer 88, 1844–1850 (2003). Report of the clinical trial of DMXAA that discusses some of the issues that have to be addressed when measuring tumour vascular effects in the clinic.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tozer, G. M. et al. Mechanisms associated with tumor vascular shutdown induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. Cancer Res. 61, 6413–6422 (2001). Detailed study of mechanisms of action of CA-4–P at the physiological level.

    CAS  PubMed  Google Scholar 

  50. Zwi, L. J., Baguley, B. C., Gavin, J. B. & Wilson, W. R. Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents. Oncol. Res. 6, 79–85 (1994).

    CAS  PubMed  Google Scholar 

  51. Galbraith, S. M. et al. Effects of combretastatin A4 phosphate on endothelial cell morphology in vitro and relationship to tumour vascular targeting activity in vivo. Anticancer Res. 21, 93–102 (2001).

    CAS  PubMed  Google Scholar 

  52. Kanthou, C. & Tozer, G. M. 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 (2002). Study of the cell-signalling events in endothelial cells in vitro , which are initiated by the effects of CA-4-P on the tubulin cytoskeleton and lead to functional changes in terms of monolayer permeability and assembly of junctional proteins.

    CAS  PubMed  Google Scholar 

  53. Tozer, G. M., Kanthou, C., Parkins, C. S. & Hill, S. A. The biology of the combretastatins as tumour vascular targeting agents. Int. J. Exp. Pathol. 83, 21–38 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Tozer, G. M. et al. Intravital imaging of tumour vascular networks using multi-photon fluorescence microscopy. Adv. Drug Deliv. Rev. 57, 135–152 (2005).

    CAS  PubMed  Google Scholar 

  55. Zhao, L., Ching, L. M., Kestell, P., Kelland, L. R. & Baguley, B. C. Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4–acetic acid (DMXAA): Increased tumor vascular permeability. Int. J. Cancer (in the press).

  56. Milosevic, M. F., Fyles, A. W. & Hill, R. P. The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis. Int. J. Radiat. Oncol. Biol. Phys. 43, 1111–1123 (1999). An instructive analysis of the role of interstitial fluid pressure in the control of tumour blood flow.

    CAS  PubMed  Google Scholar 

  57. Blakey, D. C. et al. Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. Clin. Cancer Res. 8, 1974–1983 (2002).

    CAS  PubMed  Google Scholar 

  58. Hori, K. & Saito, S. Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis. Br. J. Cancer 89, 1334–1344 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Less, J. R., Skalak, T. C., Sevick, E. M. & Jain, R. K. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res. 51, 265–273 (1991).

    CAS  PubMed  Google Scholar 

  61. Lominadze, D. & Mchedlishvili, G. Red blood cell behavior at low flow rate in microvessels. Microvasc. Res. 58, 187–189 (1999).

    CAS  PubMed  Google Scholar 

  62. Dudek, S. M. & Garcia, J. G. Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487–1500 (2001).

    CAS  PubMed  Google Scholar 

  63. Dejana, E., Spagnuolo, R. & Bazzoni, G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb. Haemost. 86, 308–315 (2001).

    CAS  PubMed  Google Scholar 

  64. Dvorak, H. F., Nagy, J. A., Dvorak, J. T. & Dvorak, A. M. Identification and characerization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am. J. Pathol. 133, 95–109 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lum, H. & Malik, A. B. Mechanisms of increased endothelial permeability. Can. J. Physiol. Pharmacol. 74, 787–800 (1996).

    CAS  PubMed  Google Scholar 

  66. Bates, D. O. & Harper, S. J. Regulation of vascular permeability by vascular endothelial growth factors. Vascul. Pharmacol. 39, 225–237 (2002).

    CAS  PubMed  Google Scholar 

  67. Su, M. Y. et al. Pharmacokinetic changes induced by vasomodulators in kidneys, livers, muscles, and implanted tumors in rats as measured by dynamic Gd-DTPA-enhanced MRI. Magn. Reson. Med. 36, 868–877 (1996).

    CAS  PubMed  Google Scholar 

  68. Johansson, M., Henriksson, R., Bergenheim, A. T. & Koskinen, L. O. Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma. Br. J. Cancer 83, 826–832 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Wojciak-Stothard, B. & Ridley, A. J. Rho GTPases and the regulation of endothelial permeability. Vascul. Pharmacol. 39, 187–199 (2002).

    CAS  PubMed  Google Scholar 

  70. Garcia, J. G., Davis, H. W. & Patterson, C. E. Regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation. J. Cell Physiol. 163, 510–522 (1995).

    CAS  PubMed  Google Scholar 

  71. Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).

    CAS  PubMed  Google Scholar 

  72. Verin, A. D. et al. Microtubule disassembly increases endothelial cell barrier dysfunction: role of MLC phosphorylation. Am. J. Physiol. Lung Cell Mol. Physiol. 281, L565–L574 (2001).

    CAS  PubMed  Google Scholar 

  73. Ye, L. H. et al. Myosin light-chain kinase of smooth muscle stimulates myosin ATPase activity without phosphorylating myosin light chain. Proc. Natl Acad. Sci. USA 96, 6666–6671 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Brooks, A. C. et al. The vascular targeting agent combretastatin A-4-phosphate induces neutrophil recruitment to endothelial cells in vitro. Anticancer Res. 23, 3199–3206 (2003).

    CAS  PubMed  Google Scholar 

  75. Parkins, C. S., Holder, A. J., Hill, S. A., Chaplin, D. J. & Tozer, G. M. Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide. Br. J. Cancer 83, 811–816 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Korbelik, M. & Cecic, I. Contribution of myeloid and lymphoid host cells to the curative outcome of mouse sarcoma treatment by photodynamic therapy. Cancer Lett. 137, 91–98 (1999).

    CAS  PubMed  Google Scholar 

  77. Prise, V. E., Honess, D. J., Stratford, M. R. L., Wilson, J. & Tozer, G. M. The vascular response of tumor and normal tissues in the rat to the vascular targeting agent, combretastatin A-4-phosphate, at clinically relevant doses. Int. J. Oncol. 21, 717–726 (2002).

    CAS  PubMed  Google Scholar 

  78. Nihei, Y. et al. Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy. Jpn. J. Cancer Res. 90, 1387–1396 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Baguley, B. C., Zhuang, L. & Kestell, P. Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine: relation to vascular effects. Oncol. Res. 9, 55–60 (1997).

    CAS  PubMed  Google Scholar 

  80. Alexander, J. S., Hechtman, H. B. & Shepro, D. Serotonin induced actin polymerization and association with cytoskeletal elements in cultured bovine aortic endothelium. Biochem. Biophys. Res. Commun. 143, 152–158 (1987).

    CAS  PubMed  Google Scholar 

  81. Lash, C. J. et al. Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs. Br. J. Cancer 78, 439–445 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ahmed, B. et al. Vascular targeting effect of combretastatin A-4 phosphate dominates the inherent angiogenesis inhibitory activity. Int. J. Cancer 105, 20–25 (2003).

    CAS  PubMed  Google Scholar 

  83. Iyer, S. et al. Induction of apoptosis in proliferating human endothelial cells by the tumor-specific antiangiogenesis agent combretastatin A-4. Cancer Res. 58, 4510–4514 (1998).

    CAS  PubMed  Google Scholar 

  84. Kanthou, C. et al. The tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death. Am. J. Pathol. 165, 1401–1411 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hill, S. A., Chaplin, D. J., Lewis, G. & Tozer, G. M. Schedule dependence of combretastatin A4 phosphate in transplanted and spontaneous tumour models. Int. J. Cancer 102, 70–74 (2002).

    CAS  PubMed  Google Scholar 

  86. Ching, L. M. et al. Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid. Br. J. Cancer 86, 1937–1942 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Sheng, Y. et al. Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis. Int. J. Cancer 111, 604–610 (2004).

    CAS  PubMed  Google Scholar 

  88. Kirwan, I. G. et al. Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate. Clin. Cancer Res. 10, 1446–1453 (2004).

    CAS  PubMed  Google Scholar 

  89. Cao, Z., Baguley, B. C. & Ching, L. M. Interferon-inducible protein 10 induction and inhibition of angiogenesis in vivo by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Res. 61, 1517–1521 (2001).

    CAS  PubMed  Google Scholar 

  90. Zhao, L., Ching, L. M., Kestell, P. & Baguley, B. C. Improvement of the antitumor activity of intraperitoneally and orally administered 5,6-dimethylxanthenone-4-acetic acid by optimal scheduling. Clin. Cancer Res. 9, 6545–6550 (2003).

    CAS  PubMed  Google Scholar 

  91. Hendrix, M. J. et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc. Natl Acad. Sci. USA 98, 8018–8023 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhao, L. S., Edgar, E., Marshall, L., Kelland, L. & Baguley, B. C. Inhibition of vasculogenic mimicry in melanoma by the antivascular drug 5,6-dimethylxanthenone-4–acetic acid (DMXAA). Eur. J. Cancer Suppl. 2 (8), 47 (2004).

    Google Scholar 

  93. Ching, L. M. et al. Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice. Cancer Res. 59, 3304–3307 (1999). Gives an introduction to the role of cytokines in the action of DMXAA.

    CAS  PubMed  Google Scholar 

  94. Wang, L. C. et al. Induction of tumour necrosis factor and interferon-g in cultured murine splenocytes by the antivascular agent DMXAA and its metabolites. Biochem. Pharmacol. 67, 937–945 (2004).

    CAS  PubMed  Google Scholar 

  95. Kallinowski, F., Schaefer, C., Tyler, G. & Vaupel, P. In vivo targets of recombinant human tumour necrosis factor-α: blood flow, oxygen consumption and growth of isotransplanted rat tumours. Br. J. Cancer 60, 555–560 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Murata, R., Overgaard, J. & Horsman, M. R. Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues. Int. J. Radiat. Biol. 77, 195–204 (2001).

    CAS  PubMed  Google Scholar 

  97. Denekamp, J. & Hobson, B. Endothelial cell proliferation in experimental tumours. Br. J. Cancer 46, 711–720 (1982). One of a series of papers by this author setting out the principles and potential for therapeutic targeting of the tumour vasculature, which was influential in stimulating research in this field.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Eberhard, A. et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388–1393 (2000).

    CAS  PubMed  Google Scholar 

  99. Park, J. H. et al. Hypoxia/aglycemia increases endothelial permeability: role of second messengers and cytoskeleton. Am. J. Physiol. 277, C1066–C1074 (1999).

    CAS  PubMed  Google Scholar 

  100. Paria, B. C. et al. Tumor necrosis factor-alpha-induced TRPC1 expression amplifies store-operated Ca2+ influx and endothelial permeability. Am. J. Physiol. Lung Cell Mol. Physiol. 287, L1303–L1313 (2004).

    CAS  PubMed  Google Scholar 

  101. Michel, C. C. & Curry, F. E. Microvascular permeability. Physiol. Rev. 79, 703–761 (1999). An excellent comprehensive review of microvascular permeability from the molecular to the physiological level.

    CAS  PubMed  Google Scholar 

  102. Tiruppathi, C., Minshall, R. D., Paria, B. C., Vogel, S. M. & Malik, A. B. Role of Ca2+ signaling in the regulation of endothelial permeability. Vascul. Pharmacol. 39, 173–185 (2002).

    CAS  PubMed  Google Scholar 

  103. Beauregard, D. A., Hill, S. A., Chaplin, D. J. & Brindle, K. M. The susceptibility of tumors to the antivascular drug combretastatin A4 phosphate correlates with vascular permeability. Cancer Res. 61, 6811–6815. (2001).

    CAS  PubMed  Google Scholar 

  104. Otani, M. et al. TZT-1027, an antimicrotubule agent attacks tumor vasculature and induces tumor cell death. Japn. J. Cancer Res. 91, 837–844 (2000).

    CAS  Google Scholar 

  105. Lew, Y. S., Brown, S. L., Griffin, R. J., Song, C. W. & Kim, J. H. Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown. Cancer Res. 59, 6033–6037 (1999).

    CAS  PubMed  Google Scholar 

  106. Davis, P. D. et al. ZD6126: a novel vascular-targeting agent that causes destruction of tumor vasculature. Cancer Res. 62, 7247–7253 (2002).

    CAS  PubMed  Google Scholar 

  107. Segreti, J. A. et al. Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study. Cancer Chemother. Pharmacol. 54, 273–281 (2004).

    CAS  PubMed  Google Scholar 

  108. Kasibhatla, S. et al. Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity. Mol. Cancer Ther. 3, 1365–1374 (2004).

    CAS  PubMed  Google Scholar 

  109. Corada, M. et al. A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood 100, 905–911 (2002).

    CAS  PubMed  Google Scholar 

  110. Blaschuk, O. W. & Rowlands, T. M. Cadherins as modulators of angiogenesis and the structural integrity of blood vessels. Cancer Metastasis Rev. 19, 1–5 (2000).

    CAS  PubMed  Google Scholar 

  111. Abramovitch, R., Dafni, H., Smouha, E., Benjamin, L. E. & Neeman, M. In vivo prediction of vascular susceptibility to vascular susceptibility endothelial growth factor withdrawal: magnetic resonance imaging of C6 rat glioma in nude mice. Cancer Res. 59, 5012–5016 (1999).

    CAS  PubMed  Google Scholar 

  112. Ashrafpour, H. et al. Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature. Am. J. Physiol. Heart. Circ. Physiol. 286, H946–H954 (2004).

    CAS  PubMed  Google Scholar 

  113. Inai, T. et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 165, 35–52 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Thorpe, P. E. Vascular targeting agents as cancer therapeutics. Clin. Cancer Res. 10, 415–427 (2004).

    PubMed  Google Scholar 

  115. Dowlati, A. et al. A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res. 62, 3408–3416 (2002).

    CAS  PubMed  Google Scholar 

  116. Gadgeel, S. M., LoRusso, P. M., Wozniak, A. J. & Wheeler, C. A dose-escalation study of the novel vascular–targeting agent, ZD6126, in patients with solid tumors. in Proc. Am. Soc. Clin. Oncol. 24, 438 (2002).

    Google Scholar 

  117. Galbraith, S. M. et al. Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J. Clin. Oncol. 20, 3826–3840 (2002).

    CAS  PubMed  Google Scholar 

  118. Anderson, H. L. et al. Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate. J. Clin. Oncol. 21, 2823–2830 (2003).

    CAS  PubMed  Google Scholar 

  119. Galbraith, S. M. et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J. Clin. Oncol. 21, 2831–2842 (2003). Report of the magnetic-resonance-imaging studies in the UK-based Phase I and II clinical trial of CA-4-P. This report shows that the pattern of vascular effects observed in humans is very similar to that predicted from animal studies.

    CAS  PubMed  Google Scholar 

  120. Stevenson, J. P. et al. Phase I trial of the antivascular agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J. Clin. Oncol. 21, 4428–4438 (2003).

    CAS  PubMed  Google Scholar 

  121. Tolcher, A. W. et al. Phase I, pharmacokinetic, and DCE-MRI correlative study of AVE8062A, an antivascular combretastatin analogue, administered weekly for 3 weeks every 28 days. in Proc. Am. Soc. Clin. Oncol. 22, 834 (2003).

    Google Scholar 

  122. Evelhoch, J. L. et al. Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin. Cancer Res. 10, 3650–3657 (2004).

    CAS  PubMed  Google Scholar 

  123. Young, S. L. & Chaplin, D. J. Combretastatin A4 phosphate: background and current clinical status. Expert Opin. Investig. Drugs 13, 1171–1182 (2004).

    CAS  PubMed  Google Scholar 

  124. Steel, G. G. & Peckham, M. J. Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int. J. Radiat. Oncol. Biol. Phys. 5, 85–91 (1979).

    CAS  PubMed  Google Scholar 

  125. Siemann, D. W. Vascular targeting agents. Horizons in Cancer Therapeutics: from Bench to Bedside 3, 4–15 (2002).

    Google Scholar 

  126. Cooney, M. M. et al. Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer. Clin. Cancer Res. 10, 96–100 (2004).

    CAS  PubMed  Google Scholar 

  127. Rustin, G. J. et al. 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: phase I clinical and pharmacokinetic study. Br. J. Cancer 88, 1160–1167 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Li, L., Rojiani, A. & Siemann, D. Targeting the tumor vasculature with combretastatin A-4 disodium phosphate: effects on radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 42, 899–903 (1998).

    CAS  PubMed  Google Scholar 

  129. Wilson, W. R., Li, A. E., Cowan, D. S. & Siim, B. G. Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid. Int. J. Radiat. Oncol. Biol. Phys. 42, 905–908 (1998).

    CAS  PubMed  Google Scholar 

  130. Horsman, M. R. et al. Combretastatins: novel vascular targeting drugs for improving anti-cancer therapy. Combretastatins and conventional therapy. Adv. Exp. Med. Biol. 476, 311–323 (2000).

    CAS  PubMed  Google Scholar 

  131. Landuyt, W. et al. In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment. Int. J. Radiat. Oncol. Biol. Phys. 49, 443–450 (2001).

    CAS  PubMed  Google Scholar 

  132. Murata, R., Siemann, D. W., Overgaard, J. & Horsman, M. R. Improved tumor response by combining radiation and the vascular-damaging drug 5,6-dimethylxanthenone-4-acetic acid. Radiat. Res. 156, 503–509 (2001).

    CAS  PubMed  Google Scholar 

  133. Murata, R., Siemann, D. W., Overgaard, J. & Horsman, H. R. Interaction between combretastatin A-4 disodium phosphate and radiation in murine tumors. Radiother. Oncol. 60, 155–161 (2001).

    CAS  PubMed  Google Scholar 

  134. Siemann, D. W. & Rojiani, A. M. Enhancement of radiation therapy by the novel vascular targeting agent ZD6126. Int. J. Radiat. Oncol. Biol. Phys. 53, 164–171 (2002).

    CAS  PubMed  Google Scholar 

  135. Siemann, D. W., Mercer, E., Lepler, S. & Rojiani, A. M. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy. Int. J. Cancer 99, 1–6 (2002).

    CAS  PubMed  Google Scholar 

  136. Bilenker, J. H. et al. Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin. Cancer Res. 11, 1527–1533 (2005).

    CAS  PubMed  Google Scholar 

  137. Jain, R. K. Delivery of molecular medicine to solid tumors. Science 271, 1079–1080 (1996).

    CAS  PubMed  Google Scholar 

  138. Pedley, R. B. et al. Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent. Cancer Res. 59, 3998–4003 (1999).

    CAS  PubMed  Google Scholar 

  139. Pedley, R. B. et al. Synergy between vascular targeting agents and antibody-directed therapy. Int. J. Radiat. Oncol. Biol. Phys. 54, 1524–1531 (2002).

    CAS  PubMed  Google Scholar 

  140. Grosios, K., Loadman, P. M., Swaine, D. J., Pettit, G. R. & Bibby, M. C. Combination chemotherapy with combretastatin A-4 phosphate and 5-fluorouracil in an experimental murine colon adenocarcinoma. Anticancer Res. 20, 229–234 (2000).

    CAS  PubMed  Google Scholar 

  141. Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).

    CAS  PubMed  Google Scholar 

  142. Wachsberger, P., Burd, R. & Dicker, A. P. Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin. Cancer Res. 9, 1957–1971 (2003).

    CAS  PubMed  Google Scholar 

  143. Siemann, D. W. & Horsman, M. R. Targeting the tumor vasculature: a strategy to improve radiation therapy. Expert. Rev. Anticancer Ther. 4, 321–327 (2004). An excellent review of the interaction of vascular-targeting agents with radiotherapy and the issues that need to be addressed.

    CAS  PubMed  Google Scholar 

  144. El-Emir, E. et al. Tumour parameters affected by combretastatin A-4 phosphate therapy in a human colorectal xenograft model in nude mice. Eur. J. Cancer 41, 799–806 (2005).

    CAS  PubMed  Google Scholar 

  145. Wachsberger, P. R. et al. Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. Clin. Cancer. Res. 11, 835–842 (2005).

    CAS  PubMed  Google Scholar 

  146. Boehle, A. S., Sipos, B., Kliche, U., Kalthoff, H. & Dohrmann, P. Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model. Ann. Thorac. Surg. 71, 1657–1665 (2001).

    CAS  PubMed  Google Scholar 

  147. Siemann, D. W. & Shi, W. Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors. Int. J. Radiat. Oncol. Biol. Phys. 60, 1233–1240 (2004).

    CAS  PubMed  Google Scholar 

  148. Siim, B. G., Denny, W. A. & Wilson, W. R. Nitro reduction as an electronic switch for bioreductive drug activation. Oncol. Res. 9, 357–369 (1997).

    CAS  PubMed  Google Scholar 

  149. Theys, J. et al. Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum. Cancer Gene Ther. 8, 294–297 (2001).

    CAS  PubMed  Google Scholar 

  150. Kobayashi, H. et al. Expression of α-smooth muscle actin in benign or malignant ovarian tumors. Gyn. Oncol. 48, 308–313 (1993).

    CAS  Google Scholar 

  151. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Paku, S. & Paweletz, N. First steps of tumor-related angiogenesis. Lab. Invest. 65, 334–346 (1991).

    CAS  PubMed  Google Scholar 

  153. Baluk, P., Morikawa, S., Haskell, A., Mancuso, M. & McDonald, D. M. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am. J. Pathol. 163, 1801–1815 (2003).

    PubMed  PubMed Central  Google Scholar 

  154. Jain, R. K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6, 559–593 (1987).

    CAS  PubMed  Google Scholar 

  155. Dvorak, H. F., Nagy, J. A. & Dvorak, A. M. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3, 77–85 (1991).

    CAS  PubMed  Google Scholar 

  156. Boucher, Y., Baxter, L. T. & Jain, R. K. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 50, 4478–4484 (1990).

    CAS  PubMed  Google Scholar 

  157. Jain, R. K. & Ward-Hartley, K. Tumor blood flow- characterization, modifications and role in hyperthermia. IEEE Trans. on sonics & ultrasonics SU-31, 504–526 (1984).

    Google Scholar 

  158. Gillies, R. J., Schornack, P. A., Secomb, T. W. & Raghunand, N. Causes and effects of heterogenous perfusion in tumors. Neoplasia 1, 197–207 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Konerding, M. A. et al. Evidence for characteristic vascular patterns in solid tumours: quantitative studies using corrosion casts. Br. J. Cancer 80, 724–732 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Sevick, E. M. & Jain, R. K. Geometric resistance to blood flow in solid tumors ex vivo: effects of tumor size and perfusion pressure. Cancer Res. 49, 3506–3512 (1989).

    CAS  PubMed  Google Scholar 

  161. Lominadze, D. & Mchedlishvili, G. Red blood cell behaviour at low flow rate in microvessels. Microvasc. Res. 58, 187–189 (1999).

    CAS  PubMed  Google Scholar 

  162. Tozer, G. M., Lewis, S., Michalowski, A. & Aber, V. The relationship between regional variations in blood flow and histology in a transplanted rat fibrosarcoma. Br. J. Cancer 61, 250–257 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Mueller-Klieser, W., Vaupel, P. & Manz, R. Intracapillary oxyhemoglobin saturation of malignant tumors in humans. Int. J. Radiat. Oncol. Biol. Phys. 7, 1397–1404 (1981).

    CAS  PubMed  Google Scholar 

  164. Vaupel, P. & Hockel, M. Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance. Int. J. Oncol. 17, 869–879 (2000).

    CAS  PubMed  Google Scholar 

  165. Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022–7032 (1988). An excellent analysis of the role of interstitial pressure in the delivery of macromolecules to tumour tissue.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research from the first two authors who contributed to this review was carried out at the Gray Cancer Institute in London, United Kingdom, and we are grateful to the Institute for providing all the necessary facilities for this work. We would also like to thank all our past and present colleagues at the Gray Cancer Institute, Mount Vernon Hospital, the Auckland Cancer Society Research Centre and elsewhere, who collaborated in our research that contributed to this review. The authors' work is supported by grants from Cancer Research UK (G.M.T and C.K.) and the Auckland Division of the Cancer Society of New Zealand (B.C.B.).

Author information

Authors and Affiliations

  1. Division of Clinical Sciences, Academic Unit of Surgical Oncology, University of Sheffield, Floor K, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK

    Gillian M. Tozer & Chryso Kanthou

  2. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand

    Bruce C. Baguley

Authors
  1. Gillian M. Tozer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chryso Kanthou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce C. Baguley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gillian M. Tozer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

TNF

TRPC1

VEGF

Cancer.gov

acute promyelocytic leukemia

FURTHER INFORMATION

Anherex

Antisoma (UK)

Astrazenica

Aventis Pharma (US site)

Cell Therapeutics

Maxim Pharmaceuticals

National Institutes of Health Clinical Trials website

Nereus Pharmaceuticals

OxiGene

Pfizer

Glossary

AMINOPEPTIDASE

An enzyme involved in protein degradation that hydrolyses peptides by acting on the peptide bond next to a terminal amino acid containing a free amino group.

ECTOPICALLY

In an abnormal place, in this case outside the tissue of origin.

ORTHOTOPICALLY

In the normal place, in this case within the tissue of origin.

DOSE POTENT

Very effective for a given dose.

BLEB

An actin-lined cell-surface protrusion.

HAEMATOCRIT

The ratio of the volume of packed red blood cells to the volume of whole blood.

ROULEAUX

A group of red blood cells resembling a stack of coins.

PROTEIN EXTRAVASATION

Movement of blood-borne protein across the vascular wall into the tissue interstitium.

PARACELLULAR PERMEABILITY

Permeability associated with solute or water transport between cells.

TRANSCELLULAR PERMEABILITY

Permeability associated with solute or water transport across the cells themselves.

PLATELET ACTIVATION

Processes involved with initiating the platelet's contribution to blood clotting.

RHEOLOGICAL

Relating to the flowing of red cells.

PERICYTES

Cells of the connective tissue strongly associated with small blood vessels.

VASOVAGAL SYNCOPE

A usually transitory condition that is marked by anxiety, nausea, respiratory distress and fainting, and that is believed to be due to joint vasomotor and vagal disturbances.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tozer, G., Kanthou, C. & Baguley, B. Disrupting tumour blood vessels. Nat Rev Cancer 5, 423–435 (2005). https://doi.org/10.1038/nrc1628

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1628

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing