Desferri-exochelin induces death by apoptosis in human breast cancer cellsbut does not kill normal breast cells

A major goal of cancer chemotherapy is the identification of cytotoxic comp ounds that are highly selective for cancer cells. We describe here one such compound - a novel iron chelator, desferri-exochelin 772SM. This desferri- exochelin has unique chemical and pharmacological properties, including ext remely high iron binding affinity, the capacity to block iron-mediated redo x reactions, and lipid solubility which enables it to enter cells rapidly. At low concentrations, this desferri-exochelin kills T47D-YB and MCF-7 huma n breast cancer cells by inducing apoptosis, but only reversibly arrests th e growth of normal human mammary epithelial cells without cytotoxicity. Sin ce iron-loaded exochelin is ineffective, iron chelation accounts for the ef ficacy of desferri-exochelin. For both the killing of breast cancer cells a nd the growth arrest of normal breast epithelial cells, desferri-exochelin was effective at much lower concentrations than the lipid-insoluble iron ch elator deferoxamine, which has shown only limited potential as an anti-canc er agent. Growth arrest of progesterone receptor positive T47D-YB cells wit h the progestin R5020 transiently protects them from the cytotoxic effects of desferri-exochelin, but the cells are killed after cell growth resumes. Similarly, MCF-7 cells arrested with the estrogen antagonist ICI182780 are transiently resistant to killing by desferri-exochelin. Thus the desferri-e xochelin is cytotoxic only to actively growing tumor cells. Since desferri- exochelin 772SM can selectively and efficiently destroy proliferating cance r cells without damaging normal cells, it may prove useful for the treatmen t of cancer.