Abstract
Several previously identified inhibitors of angiogenesis have been epoxide-containing fungus-derived metabolites. We therefore hypothesized that novel epoxide-containing low molecular weight compounds structurally resembling known antiangiogenic agents may also exhibit antiangiogenic activity. Cytochalasin E was found to be a potent and selective inhibitor of bovine capillary endothelial (BCE) cell proliferation. Cytochalasin E differed from other cytochalasins by the presence of an epoxide. The epoxide was required for activity, because acid-catalyzed hydrolysis of the epoxide abrogated the specificity and potency of cytochalasin E. Phalloidin staining indicated that disruption of actin stress fibers by cytochalasin E occurred only at relatively high concentrations. Lower concentrations of cytochalasin E preferentially inhibited BCE cell proliferation without disrupting actin stress fibers. In vivo, cytochalasin E inhibited angiogenesis induced by basic fibroblast growth factor by 40% to 50% in the mouse cornea assay and inhibited the growth of Lewis lung tumors by approximately 72%. Cytochalasin E is a potent antiangiogenic agent that may hold promise for the treatment of cancer and other types of pathologic angiogenesis.
Footnotes
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Send reprint requests to: Dr. Robert J. D'Amato, Department of Surgical Research, Enders-1022, Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115. E-mail:damato_r{at}a1.tch.harvard.edu
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↵1 This publication was supported by grants from EntreMed (to T.U. and R.J.D.), by Grant MCB9512655 from the National Science Foundation (to Y.H.C.), and by Grant 1-F32-CA-74482-01 from the National Cancer Institute (to T.U.).
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↵2 Present address: St. Louis University School of Medicine, Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis, MO 63104.
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↵3 Present address: Entremed, Inc., Rockville, MD 20850.
- Abbreviations:
- BCE
- bovine capillary endothelial
- bFGF
- basic fibroblast growth factor
- VEGF
- vascular endothelial growth factor
- DMSO
- dimethyl sulfoxide
- TRITC
- tetramethylrhodamine isothiocyanate
- MetAP-2
- methionyl aminopeptidase-2
- T/C
- tumor volume of treated animals/tumor volume of control animals
- Received January 6, 2000.
- Accepted March 30, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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