Synthesis of Targeted Drugs for Treating Breast Cancer
Annual rept. 1 Apr 2002-31 Mar 2003
UTAH UNIV SALT LAKE CITY
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New chemotherapeutic agents are needed for the improved treatment of breast cancer. In this proposal, we disclose a new approach to the design of anti-cancer drugs. Our method is to synthesize new drug conjugates that incorporate 1 a specific breast cancer cell -targeting component 2 a rapid cell membrane translocating nuclear localization moiety and 3 the capability to counter multi-drug resistance mediated by P-glycoprotein and related cellular efflux pumps. The conjugates are prepared in a few synthetic steps from available components. The goal is to demonstrate a proof-of-concept of the effectiveness of this multi-functional drug hypothesis. Specific cancer cell-targeted compounds have been prepared from the breast cancer drug doxorubicin. This cytotoxic agent is covalently linked to a synthetic arginine-glycine- aspartic acid peptidomimetic, which recognizes and binds to avb3 integrin. This receptor is overexpressed on the surface of breast cancer metastatic cells and tumors. The design also includes incorporation of the Tat peptide analog, H2Narginine7COOH, as a rapid cell membrane translocation and effective nuclear localization moiety. The new drugs will be evaluated in breast cancer cell-lines in vitro and in vivo using human breast cancer xenografts in nude mice.
- Medicine and Medical Research