cytochalasin-e and Carcinoma--Lewis-Lung

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.

Topics: 3T3 Cells; Aminopeptidases; Angiogenesis Inhibitors; Animals; Aspergillus; Carcinoma, Lewis Lung; Cell Division; Cornea; Cyclohexanes; Cytochalasins; Endothelial Growth Factors; Endothelium, Vascular; Fibroblast Growth Factor 2; Humans; Lymphokines; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mycotoxins; Neovascularization, Pathologic; Neovascularization, Physiologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors