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Drug Insight: vascular disrupting agents and angiogenesis—novel approaches for drug delivery

Nature Clinical Practice Oncology volume 3, pages 682–692 (2006)Cite this article

Abstract

Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms. Unlike antiangiogenesis agents (e.g. the monoclonal antibody bevacizumab; and tyrosine kinase inhibitors sorafenib and sunitinib) that disrupt endothelial cell survival mechanisms and the development of a new tumor blood supply, VDAs are designed to disrupt the already established abnormal vasculature that supports tumors, by targeting their dysmorphic endothelial cells. Tumor vascular endothelium is characterized by its increased permeability, abnormal morphology, disorganized vascular networks, and variable density. VDAs induce rapid shutdown of tumor blood supply, causing subsequent tumor death from hypoxia and nutrient deprivation. The safety profile of this class of compounds is more indicative of agents that are indeed 'vascularly' active. For example, VDAs can cause: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. Despite these cardiovascular concerns some patients have benefited from VDAs in early clinical trials. Further drug development of VDAs must include the combination of these agents with other novel biological agents, cytotoxic chemotherapy, and radiotherapy. Close monitoring of patients receiving VDAs for any cardiovascular toxicity is imperative.

Key Points

  • Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms

  • The safety profile for this class of compounds is more indicative of agents that are vascularly active, including: acute coronary syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient hot flashes; neuropathy; and tumor pain

  • VDAs lack the traditional cytotoxic side effects such as myelosuppression, stomatitis, mucositis, and alopecia

  • Clinical trials of a variety of VDAs, including combretastatin, DMXAA, Exherin®, TZT-1027, and ZD6126, are currently ongoing

  • Vascular strategies employing either VDAs or antiangiogenesis agents might improve cytotoxic drug delivery through normalization of tumor blood flow and enhance the effects of combined modality approaches with radiation

  • VDAs and other angiogenesis inhibitors have the potential to exploit the unique biologic properties of tumor vascular endothelium versus normal vessels

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Figure 1: Schema depicting mechanism of action of vascular disrupting agents (VDAs).
Figure 2: Schema depicting tumor vascular normalization as proposed by Jain.10
Figure 3: Preclinical data demonstrating the increase of efficacy of radiotherapy when combined with DMXAA, a vascular disrupting agent, compared with radiotherapy alone.42
Figure 4: Preclinical human models of human renal cell carcinoma in nude mice demonstrate that the combination of a vascular endothelial growth factor inhibitor (ZD6474) in combination with a vascular disrupting agent (ZD6126) had greater antitumor effect then using either agent alone.44
Figure 5: Schema illustrating several mechanisms of antivascular and antiangiogenic approaches (e.g. VDAs, monoclonal antibodies, and small molecule TKIs) currently under evaluation in the clinic by the Developmental Therapeutics Program, Case Comprehensive Cancer Center.

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Authors and Affiliations

  1. Assistant Professor,

    Matthew M Cooney, Willem van Heeckeren, Shyam Bhakta, Jose Ortiz & Scot C Remick

  2. Fellow in the Division of Hematology and Oncology,

    Matthew M Cooney, Willem van Heeckeren, Shyam Bhakta, Jose Ortiz & Scot C Remick

  3. Division of Cardiology,

    Matthew M Cooney, Willem van Heeckeren, Shyam Bhakta, Jose Ortiz & Scot C Remick

  4. Assistant Professor of Medicine–Cardiology at the Case School of Medicine,

    Matthew M Cooney, Willem van Heeckeren, Shyam Bhakta, Jose Ortiz & Scot C Remick

  5. Dr Lester E Coleman Chair in Cancer Research and Therapeutics and Associate Director of Clinical Research at the Case Comprehensive Cancer Center, and Professor of Medicine, Oncology and Global Health and Diseases at the Case School of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA

    Matthew M Cooney, Willem van Heeckeren, Shyam Bhakta, Jose Ortiz & Scot C Remick

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Correspondence to Matthew M Cooney.

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SC Remick has received research funding from Oxigene and Medicinova. The other authors declared they have no competing interests.

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Cooney, M., van Heeckeren, W., Bhakta, S. et al. Drug Insight: vascular disrupting agents and angiogenesis—novel approaches for drug delivery. Nat Rev Clin Oncol 3, 682–692 (2006). https://doi.org/10.1038/ncponc0663

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