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JNCI Journal of the National Cancer Institute 1994 86(9):700-705; doi:10.1093/jnci/86.9.700
© 1994 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 86, No. 9, 700-705, May 4, 1994
© 1994 Oxford University Press

MDR1 Gene Expression: Its Effect on Drug Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cell Lines

Jae-Gahb Park, Sung-Kyu Lee, Inn-Gyu Hong, Hun-Sik Kim, Kyoung-Hwa Lim, Kuk-Jin Choe, Woo-Ho Kim, Yong-Il Kim, Takashi Tsuruo, Michael M. Gottesman

Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University College of Medicine Seoul, Korea
Department of Pathology, Seoul National University College of Medicine Seoul
Institute of Applied Microbiology, University of Tokyo Tokyo, Japan
Laboratory of Cell Biology, National Cancer Institute Bethesda, Md

Correspondence to: Jae-Gahb Park, M. D., Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110–460, Korea.

BACKGROUND:: Hepatic tumors are resistant to many chemotherapeutic agents. Although elevated MDR1 (also known as PGY1) gene expression has been shown in such tumors, no direct association has been established between the gene expression and multidrug resistance. Purpose: To evaluate the role of the MDR1 gene in the drug resistance of hepatoma, we tested nine human hepatoma cell lines for their expression of the MDR1 gene. Methods: We measured the MDR1 messenger RNA (mRNA) expression by RNA slot-blot analysis and by immunocytochemical staining with a P-glycoprotein-specific monoclonal antibody, MRK16. The in vitro chemosensitivity of these cell lines to fluorouracil, doxorubicin, mitomy-cin C, cisplatin, and etoposide (VP-16) was determined using the MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetra-zolium bromide) colorimetric assay. For doxorubicin cytotoxicity, we also tested the potentiating effect of several multidrug resistance-reversing agents. Results: Slot-blot analysis and im-munocytochemistry showed that two cell lines expressed high levels of MDR1 mRNA, one expressed an intermediate level, and all others were low expressors. The MTT assay results showed that all cell lines tested were generally resistant to chemotherapeutic agents. The assay area under the curve (AUC) was within a clinically achievable range only for VP-16 in one of nine cell lines. When the IC50 values were compared among the cell lines, the results revealed a close association with the MDR1 gene expression only for doxorubicin resistance. Verapamil and quinidine lowered the IC50 values of doxorubicin for MDR1-positive cell lines. The lowered assay AUC levels for both reversing agents, however, were still higher than the clinically achievable range. Conclusion: These results indicate that the MDR1 gene probably has a role in doxorubicin resistance in hepatocel-lular carcinoma and that the resistance can be overcome by some multidrug resistance-reversing agents. Implications: Some widely used anticancer agents might be ineffective for treating hepatocellular carcinoma in clinical situations even when combined with reversing agents. [J Natl Cancer Inst 86: 700–705, 1994]


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