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Combretastatin A-4, an Agent That Displays Potent and Selective Toxicity toward Tumor Vasculature¹

Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom [G. G. D., S. A. H., V. E. P., G. M. T., D. J. C.], and Cancer Research Institute and Department of Chemistry, Arizona State University, Tempe, Arizona 85287 [G. R. P.]

Selective induction of vascular damage within tumors represents an emerging approach to cancer treatment. Histological studies have shown that several tubulin-binding agents can induce vascular damage within tumors but only at doses approximating the maximum tolerated dose, which has limited their clinical applicability. In this study, we show that the combretastatin A-4 prodrug induces vascular shutdown within tumors at doses less than one-tenth of the maximum tolerated dose. In vitro studies indicate that a short drug exposure results in profound long-term antiproliferative/cytotoxic effects against proliferating endothelial cells but not cells that are quiescent prior to and during drug exposure. Vascular shutdown, within experimental and human breast cancer models in vivo following systemic drug administration, was demonstrated with a reduction in functional vascular volume of 93% at 6 h following drug administration and persisted over the next 12 h, with corresponding histology consistent with hemorrhagic necrosis resulting from vascular damage. These actions against tumor vasculature and the broad therapeutic window demonstrate the clinical potential of these drugs and warrant further study to elucidate the mechanisms responsible for the antivascular effects of combretastatin A-4.

¹ This work was supported by a program grant from the Cancer Research Campaign and Outstanding Investigator Award CA 44 344-01A1-07 (to G. R. P.) from the Division of Cancer Diagnosis and Treatment, United States National Cancer Institute, Department of Health and Human Services. G. G. D. is the recipient of a Gray Laboratory Cancer Research Trust student fellowship.

² To whom requests for reprints should be addressed.

Received 2/ 3/97. Accepted 3/31/97.

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