The long-term objective of this laboratory is to investigate the role of cytokines in the endogenous immune response to cancer, with the goal of exploiting these anti-tumor responses to characterize the prognosis of, and/or design innovative treatment for, human cancers. Interferon gamma (IFN-gamma) appears from prior data to be an important endogenous mediator of the anti-tumor response. The objective of this proposal is to further define the mechanisms of the direct anti-tumor effect of IFN- gamma with particular focus on the interferon regulatory factors 1 and 2 (IRF-1 and IRF-2). Specifically: (1) To characterize the consequences of IRF-1 expression in murine tumor cell lines, murine tumor culture models expressing transfected IRF-1 will be used, with measurement of tumor growth rate in vitro, MHC expression by FACS and RT-PCR analysis, and cell cycle control. (2) To characterize the consequences of IRF-2 expression in murine tumor cell lines, murine tumor culture models expressing transfected IRF-2 will be used, with measurement of growth rate, cell cycle control and sensitivity to exogenous cytokine effects in vitro. (3) To investigate the in vivo effects of IRF-1 or IRF-2 expression in terms of growth rate, tumor immunity, sensitivity to tumor necrosis factor - (TNF), endotoxin-(LPS), and IL-12-induced tumor regression, and the effects of host immune responses on the expression of IRF-1 and IRF-2, murine in vivo tumor models will be used. (4) The basal and inducible expression of hIRF-1 and hIRF-2 in human tumor cell lines, and the presence of IRF-1 and IRF-2 expression in archival human tumor specimens will be assessed and correlated with clinical behavior. These experiments will elucidate the roles of IRF-1 and IRF-2 in tumor growth in intact, immunocompetent animals, and begin to address the potential clinical importance of IRF expression in human tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA073846-02
Application #
2871947
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Hecht, Toby T
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Connett, Judith M; Badri, Linda; Giordano, Thomas J et al. (2005) Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays. J Interferon Cytokine Res 25:587-94
Yim, John H; Ro, Simon H; Lowney, Jennifer K et al. (2003) The role of interferon regulatory factor-1 and interferon regulatory factor-2 in IFN-gamma growth inhibition of human breast carcinoma cell lines. J Interferon Cytokine Res 23:501-11
Doherty, G M; Boucher, L; Sorenson, K et al. (2001) Interferon regulatory factor expression in human breast cancer. Ann Surg 233:623-9
Lowney, J K; Boucher, L D; Swanson, P E et al. (1999) Interferon regulatory factor-1 and -2 expression in human melanoma specimens. Ann Surg Oncol 6:604-8