Introduction:
@EN MDR(multidrug resistance), which is caused by mdr gene and its product, p-glycoprotein, is one of the most important obstacles during cancer chemtherapy. Recently, many efforts to reverse MDR have been done and partly applied in clinic.
Verapamil,
quinidine, dipyridamole and cyclosporine were the representative ones and tamoxifen and toremifene have been known as those kinds. On the other hand, protein kinase c(PKC) has a critical role in cell proliferation and differentiation and also
associated
with MDR. Using wild type and adriamycin-resistant type of MCF-7(MCF/-7WT and MCF-7/ADM), we found antiestrogen, tamoxifen, had a synergistic cytotoxic effect with adriamycin on MCF-7/ADM, not on MCF-7/WT. We also tried to clarify the mechanisms
of
synergism of tamoxifen with adriamycin, especially in the viewpoint of drug uptake and PKC activity.
@ES Results:
@EN IC50 of adriamycin-cytotoxicity on MCF-7/WT and MCF-7/ADM was 0.2μg/ml and 2μg/ml, respectively. Tamoxifen moved IC50 of adriamycin-cytotoxicity of left in a dose-dependent manner in MCF-7/ADM, and 10μM concentration of tamoxifen made IC50
0.2μg/ml in that cell line, which was very similar to IC50 in MCF-7/WT. But tamoxifen did not have synergistic cytotoxicity with adriamycin on MCF-7/WT. In drug efflux study with C14-adriamycin, tamoxifen enhanced drug uptake more than 200% in
MCF-7/ADM although it markedly decreased when tamoxiten was added. There was no difference in baseline PKC activity and degree of dose-dependent inhibition on PKC activity by adriamycin in those two cell lines.
@ES Conclusion;
@EN Tamoxifen is thought to be as one of the plausible agents to reverse MDR in breast cancer. The possible mechanisms are to increase cellular uptake of adriamycin and to inhibit PKC activity.
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