Patients with advanced colo-rectal cancer respond to high dose chemotherapy with alkylating agents in sufficient numbers to provide the basis for cautious optimism that this disease can be cured with biochemical modulation of high dose chemotherapy and autologous bone marrow transplantation. We plan to define the biochemical mechanisms present in colon cancer that limit the antitumor effect of the alkylating agents Melphalan and BCNU and determine how these processes can be modulated to improve the therapy of this disease. A bank of human colon cancer cell lines will be used as models of intrinsic and acquired resistance to Melphalan and BCNU. Resistance pathways will be identified and characterized. Strategies will be developed to overcome resistance patterns primarily associated with the DNA repair pathways and Cellular protective mechanisms including glutathione transferase, thiol metabolism, O(6) alkylguanine alkyltransferase, DNA excision and cross link repair, and poly(ADP-ribose) and pyridine nucleotide metabolism. Molecular Biology studies will be performed to determine the contribution of genes for multidrug resistance, glutathione transferase, metalothione and ras activation to the alkylating agent resistant phenotype. Biochemical modulation protocols developed on the basis of these studies will be tested in vitro in tissue culture and in vivo using a xenograft model of human colon cancer in athymic mice. These studies will provide the rational basis to develop, optimize and test strategies to defeat drug resistance mechanisms. Clinical trials employing biochemical modulators with high dose chemotherapy and autologous bone marrow transplantation will be developed and tested 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 #
3094457
Study Section
Special Emphasis Panel (SRC (S1))
Project Start
1990-12-05
Project End
1995-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
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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Phillips Jr, W P; Willson, J K; Markowitz, S D et al. (1997) O6-methylguanine-DNA methyltransferase (MGMT) transfectants of a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive colon cancer cell line selectively repopulate heterogenous MGMT+/MGMT- xenografts after BCNU and O6-benzylguanine plus BCNU. Cancer Res 57:4817-23
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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