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J Korean Cancer Assoc > Volume 26(2); 1994 > Article
Journal of the Korean Cancer Association 1994;26(2): 242-249.
아드리아마이신 저항성 유방암세포주 MCF - 7 에서 에스트로젠 길항제에 의한 다제약물 내인성의 역전 : Protein Kinase C 의 역할
문한림, 김훈교, 이경식
Reversal of ( MDR ) Multidrug resistance ) in Adiamycin - Resistant MCF - 7 Cells by Tamoxifen : Possible Role of Protedin Kinase ( PCK )
Han Lim Moon, Hoon Kyo Kim, Kyung Shik Lee
ABSTRACT
Introduction: MDR(multidrug resistance), which is caused by mdr gene and its product, p-gly- coprotein, 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-7/WT and MCF-7/ADM), we found antiestrogen, tamoxifen, had a synergistic cytotoxic effect with adriamycin on MCF-7/ADM, not on MCF-1/ WT. We also tried to clarify the mechanisms of synergism of tamoxifen with adriamycin, espe- cially in the viewpoint of drug uptake and PKC activity.
Results:
IC of adriamycin-cytotoxicity on MCF-7/WT and MCF-7/ADM was 0.2 ug/ml and 2 ug/ml, respectively. Tamoxifen moved IC of adriamycin-cytotoxicity of left in a dose-dependent manner in MCF-7/ADM, and 10 pM concentration of tamoxifen made IC 0.2 pg/ml in that cell line, which was very similar to IC 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 tamoxifen 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. Canclusion; 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.
Key words: Multidrug resistance, Reversal, Tamoxifen, Protein kinase C
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