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Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007 [S. I., D. S. R., A. H. B., L-Y.L., M. E. S.], and Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom [D. J. C.]
The antiangiogenic, tubulin-binding drug combretastatin A-4 exhibits a selective toxicity for proliferating endothelial cells in vitro and induces vascular shutdown in tumor models in vivo. The mechanism of combretastatin A-4 cytotoxicity has now been investigated with cultured proliferating human umbilical vein endothelial cells by examining various markers of apoptosis. Incubation of cells with 0.1 mM combretastatin A-4 induced the conversion (first detected after 6 h) of the CPP32 proenzyme to active caspase-3, a cysteine protease that plays an important role in apoptosis in many cell types; the drug also increased caspase-3 activity. Another early event observed was the binding of annexin V to 50% of the cells 8 h after drug treatment. Internucleosomal DNA fragmentation, another hallmark of apoptosis, was detected in cells incubated with 0.1 mM combretastatin A-4 for 24 h. Staining with Hoechst 33258 revealed that about 75% of cells exhibited a nuclear morphology characteristic of apoptosis after incubation with drug for 24 h. Incubation of cells for up to 8 h with combretastatin A-4 did not induce the release of lactate dehydrogenase or increase the uptake of propidium iodide, both indicators of membrane integrity. These results indicate that the selective cytotoxic effect of combretastatin A-4 is mediated by the induction of apoptosis rather than by necrosis and may provide an enhanced clinical strategy in cancer chemotherapy with this new agent.
1 This work was supported by Grant 97A108 (to M. S.) and Grant 97A105-107 (to D. J. C.) from Oxigene, Inc., Lund, Sweden.
2 To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Georgetown School of Medicine, Basic Science Building, Room 351, 3900 Reservoir Road, NW, Washington, DC 20007. Phone: (202) 687-1718; Fax: (202) 687-7186; E-mail: smulson@bc.georgetown.edu.
Received 7/17/98. Accepted 8/31/98.
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