Chemomodulation of Doxorubicin Pharmacodynamics

This project aims to develop improved strategies for using doxorubicin in the treatment of multidrug resistant advanced breast cancer while simultaneously minimizing the risk of cardiotoxicity. The wild type and multidrug resistant MCF-7 human breast cancer cells were characterized and the HPLC methods standardized for use in pharmacokinetic studies. Electron paramagnetic resonance was utilized to detect free radical production by MCF-7 and MCF-7ADR cells during doxorubicin metabolism. The interaction of tamoxifen with doxorubicin was investigated in vitro. Tamoxifen potentiated the cytotoxicity of doxorubicin towards multidrug resistant MCF-7ADR cells but not the wild type MCF-7 cells. The wild type MCF-7 and its multidrug resistant variant cells yielded different amounts of free radicals as judged by spin trapping experiments when incubated with doxorubicin. The antiestrogen tamoxifen did not affect free radical production from doxorubicin. Interpretation of these results was complicated by the fact that the cell viability differed considerably in the two cell types upon treatment with doxorubicin. Tamoxifen acted as an antioxidant and inhibited free radical initiated lipid peroxidation in cardiac and hepatic microsomal preparations. Tamoxifen may reverse multidrug resistance and exert its antioxidant properties to protect against cardiac tissue damage.