Human colon cancer remains resistant to most chemotherapeutic agents. In this project we will analyze repair of O(6) alkylguanine-DNA adducts as a specific mechanism of nitrosourea resistance in colon cancer cells. Because this adduct is a major cause of the cytotoxic effects of nitrosoureas, DNA repair of this adduct may be a useful target for biochemical modulation of drug resistance. For this reason, we will study the DNA repair protein O(6) alkylguanine-DNA alkyltransferase (alkyltransferase), which repairs O(6) alkylguanine-DNA adducts. Specifically, we will establish that the alkyltransferase is an important mechanism of nitrosourea resistance in colon cancer and develop ways to modulate nitrosourea resistance in colon cancer first in vitro, then in xenografts and finally in human clinical trials by inactivating the alkyltransferase. To this end, we aim to: (1) Characterize alkyltransferase activity in colon cancer and colon cancer cell lines. (2) Evaluate the ability of alkyltransferase inhibitors to overcome nitrosourea resistance in the cell lines. (3) Determine whether modulators of other drug resistance systems affect the alkyltransferase and/or alter the action of alkyltransferase inhibitors. (4) Establish the ability of alkyltransferase modulators to sensitize colon tumor xenografts to nitrosoureas (5). Determine the myelotoxicity of each modulator/- cytotoxic drug combination studied in this Program Project at doses that look promising in the xenograft model, and (6) During clinical trials with modulators and BCNU, measure modulator blood levels and monitor the modulation of alkyltransferase achieved in tumor biopsy samples. These studies match the major theme of this Program Project, the development of rational treatment strategies to overcome alkylating agent resistance in patients with colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA051183-02
Application #
3795821
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Traicoff, J une L; Willson, James K V; Markowitz, Sanford D (2002) Early loss of deleted in colorectal carcinoma gene transcript detected in a group of benign colon adenomas. J Biomed Sci 9:716-20
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Whitacre, C M; Berger, N A (1997) Factors affecting topotecan-induced programmed cell death: adhesion protects cells from apoptosis and impairs cleavage of poly(ADP-ribose)polymerase. Cancer Res 57:2157-63
Chatterjee, S; Hirota, H; Belfi, C A et al. (1997) Hypersensitivity to DNA cross-linking agents associated with up-regulation of glucose-regulated stress protein GRP78. Cancer Res 57:5112-6
Whitacre, C M; Zborowska, E; Gordon, N H et al. (1997) Topotecan increases topoisomerase IIalpha levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res 57:1425-8

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