Chemomodulation of Doxorubicin Pharmacodynamics

Abstract : The project aims to develop;strategies for using doxorubicin in the treatment of multidrug resistant advanced breast cancer while simultaneously minimizing the risk of cardiotoxicity. The wild type MCF-7 breast cancer cells and the multidrug resistant cell line designated as MCF7/ADR were genetically unrelated. This slowed the progress of our research. However, genetically related MCF-7 wild type and its genetically related multidrug resistant variant were acquired and used successfully in our studies. We have found that in general, multidrug resistance reversing agents inhibit free radical mediated microsomal lipid peroxidation, but do not inhibit the conversion of doxorubicin to its semiquinone free radical. Several potent multidrug reversing agents have been identified. Several antiestrogens including tamoxifen sensitized drug resistant breast cancer cells to cyctoxicity of doxorubicin. The natural product tetrandrine and the anti diarrhea medicine loperamide were potent agents for reversing multidrug resistance. Both dipyridamole and raloxifene resembled tamoxifen in potentiating the cytotoxicity of doxorubicin towards MCF7/ADR cells, and inhibiting doxorubicin mediated microsomal lipid peroxidation. Raloxifene, dipyridamole and tamoxifen can inhibit protein kinase C, which is an attractive target for modulating multi drug resistance. Nicotine, which is cardiotoxic, can activate protein kinase C pathway. Raloxifene, tamoxifen and dipyridamole have basic amino groups in common, but unlike nicotine, they inhibit protein kinase C and sensitize multidrug resistant cells.