Abstract

The overall goal of this project is to determine the role of loss of DNA mismatch repair (IVIMR) in the development of cellular drug resistance in vitro and in vivo. This project focuses on the new discovery that loss of IVIIVIR causes the cells to become resistant to cisplatin and carboplatin.
The Specific Aims are directed at the following questions: 1) does treatment with cisplatin enrich for pre-existing MMR-deficient cells in a tumor population growing in vivo?; 2) does treatment with cisplatin enrich for MMR-deficient cells in patients?; 3) does loss of MMR increase the spontaneous rate of mutation to resistance to other clinically important chemotherapeutic agents?; and 4) does loss of MMR increase the ability of cisplatin to mutagenize tumor cells to other chemotherapeutic agents?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078648-04
Application #
6376889
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1998-07-01
Project End
2002-04-30
Budget Start
2001-06-19
Budget End
2002-04-30
Support Year
4
Fiscal Year
2001
Total Cost
$224,725
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Larson, Christopher A; Blair, Brian G; Safaei, Roohangiz et al. (2009) The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol Pharmacol 75:324-30
Lin, Xinjian; Okuda, Tsuyoshi; Trang, Julie et al. (2006) Human REV1 modulates the cytotoxicity and mutagenicity of cisplatin in human ovarian carcinoma cells. Mol Pharmacol 69:1748-54
Cheng, Timothy C; Manorek, Gerald; Samimi, Goli et al. (2006) Identification of genes whose expression is associated with cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 58:384-95
Lin, Xinjian; Trang, Julie; Okuda, Tsuyoshi et al. (2006) DNA polymerase zeta accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost DNA mismatch repair. Clin Cancer Res 12:563-8
Okuda, Tsuyoshi; Lin, Xinjian; Trang, Julie et al. (2005) Suppression of hREV1 expression reduces the rate at which human ovarian carcinoma cells acquire resistance to cisplatin. Mol Pharmacol 67:1852-60
Safaei, Roohangiz; Katano, Kuniyuki; Larson, Barrett J et al. (2005) Intracellular localization and trafficking of fluorescein-labeled cisplatin in human ovarian carcinoma cells. Clin Cancer Res 11:756-67
Samimi, Goli; Manorek, Gerald; Castel, Rob et al. (2005) cDNA microarray-based identification of genes and pathways associated with oxaliplatin resistance. Cancer Chemother Pharmacol 55:1-11
Katano, Kuniyuki; Safaei, Roohangiz; Samimi, Goli et al. (2004) Confocal microscopic analysis of the interaction between cisplatin and the copper transporter ATP7B in human ovarian carcinoma cells. Clin Cancer Res 10:4578-88
Wu, Fang; Lin, Xinjian; Okuda, Tsuyoshi et al. (2004) DNA polymerase zeta regulates cisplatin cytotoxicity, mutagenicity, and the rate of development of cisplatin resistance. Cancer Res 64:8029-35
Samimi, Goli; Varki, Nissi M; Wilczynski, Sharon et al. (2003) Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 9:5853-9

Showing the most recent 10 out of 23 publications