The proposed research will determine the potential utility of novel high molecular weight iron chelators as anti-cancer agents or adjuncts to other iron-depriving therapeutic strategies in the treatment of cancer. This approach takes advantage of the elevated iron requirements of many types of tumors. A series of high molecular weight iron chelators consisting of the powerful iron-binding drug, deferoxamine (DFO), coupled to biocompatible polymers will be synthesized and screened for anti- neoplastic activity in vitro. Subsequently, in vivo efficacy will be determined in animal models of various cancers to determine relative anti- tumor activity. These macromolecular iron chelators will also be used in conjunction with antibodies directed against the transferrin receptor, as a means of interrupting the cellular iron acquisition system. It has been shown previously that the combination of DFO and antitransferrin receptor antibodies (ATRAs) provides-synergistic anti-tumor activity. This effect may be significantly enhanced with macromolecular deferoxamine conjugates which permit the maintenance of high vascular chelator concentrations. Finally, these macromolecular chelators wall be tested as adjuncts to cancer therapy with gallium-transferrin, a technique known to inhibit tumor growth in mice via iron deprivation.
| Kling, P J; Dragsten, P R; Roberts, R A et al. (1996) Iron deprivation increases erythropoietin production in vitro, in normal subjects and patients with malignancy. Br J Haematol 95:241-8 |
| Kemp, J D; Cardillo, T; Stewart, B C et al. (1995) Inhibition of lymphoma growth in vivo by combined treatment with hydroxyethyl starch deferoxamine conjugate and IgG monoclonal antibodies against the transferrin receptor. Cancer Res 55:3817-24 |
