Abstract

This is the first submission of an application that proposes to investigate the role of Pgp gene expression in the development of hepatocarcinogenesis (HCC) in rodent cells. Previous studies have shown that mdr1a and mdr1b expression is consistently elevated in HCC in mouse and rat, respectively. This increased expression is observed in HCC arising from both viral and carcinogenic insults, leading the applicant to suggest that multiple carcinogenic pathways """"""""converge"""""""" in the development of HCC, with Pgp gene activation as one of the end-points of this convergence. Therefore, he suggests that analysis of Pgp gene activation will provide important insights into the pathogenic pathways in the various carcinogenic programs and identify the cellular origins of HCC. Moreover, he states that the observation that different isoforms of Pgp are activated in rat versus mouse indicates that the isoforms can compensate for each other. He now proposes to 1) continue the analysis of a cell-specific enhancer element that has been identified within the mdr1b promoter; 2) develop an effective delivery system for targeting recombinant DNA into HCC and 3) investigate the role of MDR in the pathogenesis of liver cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072404-02
Application #
2700711
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Johnson, George S
Project Start
1997-05-09
Project End
2000-04-30
Budget Start
1998-06-19
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Kuo, Macus Tien (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11:99-133
Song, Im-Sook; Chen, Helen H W; Aiba, Isamu et al. (2008) Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol 74:705-13
Aiba, Isamu; Hossain, Anwar; Kuo, Macus Tien (2008) Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol 74:823-33
Chen, Helen H W; Song, Im-Sook; Hossain, Anwar et al. (2008) Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol Pharmacol 74:697-704
Kuo, Macus Tien; Chen, Helen H W; Song, Im-Sook et al. (2007) The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83
Kuo, M Tien (2007) Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 608:23-30
Kuo, M Tien; Wei, Yingjie; Yang, Xinlin et al. (2006) Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development. Biochem Biophys Res Commun 340:887-93
Wei, Yingjie; Lin-Lee, Yen-Chiu; Yang, Xinlin et al. (2006) Molecular cloning of Chinese hamster 1q31 chromosomal fragile site DNA that is important to mdr1 gene amplification reveals a novel gene whose expression is associated with spermatocyte and adipocyte differentiation. Gene 372:44-52
Tien Kuo, M; Savaraj, Niramol (2006) Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers. Mol Carcinog 45:701-9
Song, Im-Sook; Tatebe, Shigeru; Dai, Wenping et al. (2005) Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. J Biol Chem 280:28230-40

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