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Meeting Report |
Department of Pharmacology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390 [P. E. T.]; Oxigene Inc., Boston, Massachusetts 02472 [D. J. C.]; and Cancer and Infection Bioscience Department, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom [D. C. B.]
ABSTRACT
The First International Conference on Vascular Targeting focused on vascular targeting agents (VTAs) that occlude or destroy the pre-existing blood vessels of solid tumors. The VTAs cause a rapid shutdown in the blood supply to the tumor that kills tumor cells by depriving them of oxygen and nutrients. The VTAs are distinct from antiangiogenic agents, which prevent new blood vessel formation. Two major types of VTAs are being developed for cancer: the ligand-directed VTAs that use antibodies, peptides, and growth factors to deliver toxins, procoagulants, and proapoptotic effectors to tumor endothelium, and the small molecule VTAs that do not specifically localize to tumor endothelium but exploit pathophysiological differences between tumor and normal tissue endothelia to induce acute vascular shutdown in tumors. Both approaches were described at the meeting and highlighted the variety of VTAs in preclinical development, their selectivity for tumor endothelium, their rapid antitumor effects, and the improved activity seen when combined with other anticancer approaches (antiproliferative chemotherapeutic drugs, radiation, radiolabeled antibodies, nitric oxide synthetase inhibitors, and antiangiogenic agents). Early clinical studies were summarized for the small molecule VTAs: the antitubulin drugs, combretastatin A4 phosphate (CA4P) and ZD6126, and the flavonoid, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). The agents lacked the bone marrow and gastrointestinal toxicities associated with antiproliferative chemotherapy. As a marker of biological effect, blood flow reductions in tumors were measured using magnetic resonance imaging or positron emission tomography for all of the agents tested, and single-agent clinical activity was seen. These agents are now being evaluated in combined modality studies to see whether the impressive results obtained in experimental models can be translated into humans.
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