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Reversal of Multidrug Resistance in Breast Cancer

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Annual rept. 15 Mar 1993-15 Mar 1994

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Drug resistance is a major obstacle in the treatment of cancer. The multidrug resistance gene MDR1 encodes an energy dependent drug efflux pump, P170, that confers cellular resistance to multiple therapeutic agents such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxol, and actinomycin-D. MDR1 gene expression is tumor specific in both de novo resistant tumors and those that acquire drug resistance following chemotherapy. The central role of P-170 in this multidrug resistance MDR phenotype suggests that modulation of either MDR1 gene expression or the function of P-170 may provide an effective means of clinically reversing drug resistance. Our data show that MDR1 gene expression is important in breast cancer resistance. The role of the MDR1 gene in breast cancer treatment will be further defined by sequentially determining MDR1 gene expression pre- and post-treatment with doxorubicin in the context of prospective clinical trials. In addition, this study will allow a correlation of MDR1 gene expression and clinical outcome. To determine what level of MDR1 gene expression is clinically significant, various molecular methods of determining MDR1 gene expression, including immunohistochemistry and quantitative reverse transcription followed by polymerase chain reaction, will be evaluated. MDR can be reversed in vitro and recent data from the in vivo transgenic mouse model suggests that combining MDR modulators such as cyclosporine and quinine, may have an advantage over either alone. We will test this hypothesis in a Phase I study of cyclosporine A and quinine as MDR reversers of vinblastine resistance. Together these studies will address the major goal of circumventing drug resistance in breast cancer.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research
  • Pharmacology

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