Tamoxifen (TAM and 5-fluorouracil (FUra) are each commonly used agents in the treatment of breast cancer. However, they are not routinely used in vivo in such a manner that exploits their potential for synergistic interaction. This project produced the earliest published reports showing that TAM and FUra could be combined in vitro against human breast cancer cells to produce synergistic cytotoxicity. Studies have since focused on the mechanisms underlying this interaction, and the potential scope of its application. New drug-hormone combinations found to have synergistic antiproliferative activity include TAM followed by estradiol (E2) + sequenced MTX/FUra, and TAM + recombinant alpha-interferon (alpha IFN). Other drugs and mitogenic growth factors will be studied in combination with TAM, E2, and FUra looking for common biochemical mechanisms that might be associated with synergistic chemoendocrine interactions. These assays will use cultured T47-D and MCF-7 cells, as well as MCF-7 clonal variants including the TAM resistant R27 cells and five oncogene transfected subclones which over-express c-myc and are less sensitive to TAM. The project will continue to investigate RNA- and estrogen receptor (ER)- mediated interactions between TAM and FUra. ER from control and drug treated cells will be extracted looking for differences in binding affinity (kd), sedimentation (S) and isoelectric point (pI), monoclonal antibody idiotype specificity, and dependence on protease, phosphatase, and RNase inhibitors. Purified RNA from control and treated cells will be probed for expression of oncogenes (c-myc, c-fos, c- ras) and small regulatory sequences of RNA (U1, U3, 7Sk, 7SL). These studies will hopefully provide new direction for advancements in the treatment of breast cancer.
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