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Experimental Therapeutics |
Angiogene Pharmaceuticals Ltd., Oxford Science Park, Oxford, OX4 4GA [P. D. D., G. J. D.]; AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG [D. C. B.]; and Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR [S. M. G., G. M. T., A. L. H., M. A. N., J. N., M. R. L. S., D. J. C., S. A. H.], United Kingdom
Physiological differences between tumor and normal vasculature provide a target for drug discovery. In particular, the immature nature of tumor vasculature may render it intrinsically sensitive to disruption by agents affecting the endothelial cell cytoskeleton, including tubulin-binding agents. In this article, we report the synthesis of a water-soluble phosphate prodrug, ZD6126, of the tubulin-binding agent N-acetylcolchinol. In vitro studies demonstrate the comparative tubulin-binding properties of the prodrug and active drug, and show the induction of pronounced, reversible changes in endothelial cell morphology at subcytotoxic doses. Neither ZD6126 nor N-acetylcolchinol showed effects on the growth of human umbilical vein endothelial cells at concentrations below 100 µM. In contrast, changes in endothelial cell morphology were seen at much lower, noncytotoxic concentrations (0.1 µM) of ZD6126 and more pronounced effects were seen in proliferating versus confluent endothelial cell cultures. In vivo studies were carried out using a murine tumor model (CaNT) with single administration of a dose well below the maximum tolerated dose. These studies showed a large reduction in vascular volume, induction of extensive necrosis in tumors, and a reduced tumor cell yield in a clonal excision assay, consistent with vascular rather than cytotoxic effects. A viable rim of tumor remained after single-dose administration and minimal growth delay was observed. However, well-tolerated, multiple administration regimens led to pronounced tumor-growth delay. In the human xenograft FaDu, the growth delay given by a single dose of paclitaxel was enhanced by combination with a single dose of ZD6126, and the growth delay given by the combination was greater than the sum of the growth delays from the individual treatments. These findings show that ZD6126 is a promising antivascular agent for the treatment of solid tumors.
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