It has been reported that the multidrug-resistance/P-glycoprotein (mdr/pgp) gene is overexpressed in many mouse hepatocellular carcinoma (HCC) models, irrespective of carcinogenic regimens. This finding suggests that mdr gene expression may be a useful phenotypic marker to test the hypothesis that different hepatocarcinogenetic pathways in different HCC models may be converged in tumor development. To test this hypothesis, we propose here using in situ hybridization and immunocytochemical analyses to investigate mdr gene expression at the single cell level in various HCC models, including transgenic mice carrying liver targeted expression of hepatitis B viral large envelope protein gene and SV40 T-antigen gene which develope HCC following synchronous and predictable pathogenetic kinetics. This study may help us to understand the evolution of drug-resistance during hepatocarcinogenesis. Furthermore, these mouse HCC models may offer an attractive system for investigation on molecular mechanism of mdr gene activation during oncogenesis. Approaches to delineate the molecular mechanisms of mdr gene expression at transcriptional and/or posttranscriptional levels in established HCC-derived cell lines and primary HCC cells are proposed. These studies may provide important insights into the molecular basis of gene expression during hepatocarcinogenesis. In addition, we propose to determine the levels of mdr mRNA in human HCC in hoping to gain a preclinical assessment on the possible role of mdr gene expression in the intrinsic drug-resistance of this disease. This study is clinically relevant and may lead to development of effective chemotherapeutic strategy in combating human HCC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemical Pathology Study Section (CPA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
Zip Code
Zhou, G; Kuo, M T (1998) Wild-type p53-mediated induction of rat mdr1b expression by the anticancer drug daunorubicin. J Biol Chem 273:15387-94
Priebe, W; Krawczyk, M; Kuo, M T et al. (1998) Doxorubicin- and daunorubicin-glutathione conjugates, but not unconjugated drugs, competitively inhibit leukotriene C4 transport mediated by MRP/GS-X pump. Biochem Biophys Res Commun 247:859-63
Zhou, G; Kuo, M T (1997) NF-kappaB-mediated induction of mdr1b expression by insulin in rat hepatoma cells. J Biol Chem 272:15174-83
Zhou, G; Song, R; Kuo, M T (1996) A novel cis-acting element is involved in the promoter activity of the rat mdr1b gene. Cell Growth Differ 7:1369-81
Ishikawa, T; Bao, J J; Yamane, Y et al. (1996) Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 271:14981-8
Kuo, M T; Bao, J J; Curley, S A et al. (1996) Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers. Cancer Res 56:3642-4
Bao, J J; Zhang, W W; Kuo, M T (1996) Adenoviral delivery of recombinant DNA into transgenic mice bearing hepatocellular carcinomas. Hum Gene Ther 7:355-65
Song, R; Ikeguchi, M; Zhou, G et al. (1995) Identification and characterization of a hepatoma cell-specific enhancer in the mouse multidrug resistance mdr1b promoter. J Biol Chem 270:25468-74
Kuo, M T; Julian, J; Husain, F et al. (1995) Regulation of multidrug resistance gene mdr1b/mdr1 expression in isolated mouse uterine epithelial cells. J Cell Physiol 164:132-41
Zhao, J Y; Savaraj, N; Song, R et al. (1994) Overexpression of P-glycoprotein but not its mRNA in multidrug resistant cells selected with hydroxyrubicin. Anticancer Res 14:1735-42

Showing the most recent 10 out of 16 publications