This OIG seeks to consolidate two avenues of research which focus on defining mechanisms by which tumor cells develop and express resistance to drugs containing possible alkylating functions. For classical nitrogen mustards, an extension of our earlier observations on the role of glutathione S-transferases (GST) in regulating resistance through enhanced detoxification will be pursued. In different model resistant cell lines, studies on regulation and expression of the three major GST isozyme families (alpha, mu and pi) will be considered. Using a battery of cDNA probes and isozyme specific antibodies, techniques will be applied which measure enzyme induction at both the mRNA and protein levels. Other cell culture studies will elucidate the mechanism(s) by which ethacrynic acid modulates GST mediated resistance. Such information will be applied to clinical trials which are designed around this modulation concept. Additional human studies will address genetic polymorphisms in GST expression in tumor and normal cells. This pharmacogenetic approach will be related to GST isozyme expression in individual patients and will be correlated with potential response to chemotherapy. Our continuing efforts with the steroid-mustard derivative, estramustine (EM), will focus on characterization of our recently cloned estramustine resistant human prostate carcinoma cell lines. Analysis of cytoskeletal adaptations, especially with respect to tubulin and actin isoforins and altered expression of various microtubule associated proteins (MAP's) will be enacted with a view to understanding factors which may govern mitotic traverse following, or during, estramustine exposure. A novel photoaffinity analogue of EM will be used to determine potential membrane and cytoskeletal target specificities in cell lines and human biopsies generated from a Phase II EM/vinblastine trial. Such data will prove important in elucidating mechanisms of action and perhaps in predicting patient response. Additional studies will focus on the potential for taxol to enhance the chemotherapeutic value of EM. Such data would provide a framework for the design of a further antimicrotubule clinical regimen. Support for these studies would enhance and continue those facets of the PI's expertise in describing cellular mechanisms responsible for the phenotypic expression of drug resistance and applying such findings to the design or novel chemotherapeutic trials for the management of various tumor types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
3R35CA053893-07S1
Application #
6039904
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1993-05-14
Project End
2000-02-29
Budget Start
1999-03-08
Budget End
2000-02-29
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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