The development of resistance to antitumor agents is a major pitfall in cancer chemotherapy. Agents, which alone or in combination can overcome tumor resistance mechanisms, are successful chemotherapeutic agents. Recent studies indicate that the clinically used TS inhibitors 5FU, 5FdR, AD1694, and LY23154 all induce thymidylate synthase (TS) synthesis. Thus the use of traditional antifolate TS inhibitors such as ZD1694 and LY231514 prevents normal TS enzyme interaction with TS mRNA and results in enhanced TS mRNA translation and increased synthesis of new TS enzyme. This represents a potentially important mechanism for the development of clinical drug resistance to these TS inhibitors. In collaboration with Dr. Chu, the applicant has recently discovered that unlike the currently used folate inhibitors, three compounds synthesized by his group do not prevent the interaction of TS protein with TS mRNA and do not elicit increased synthesis of new enzyme. On the basis of the preliminary studies, the applicant proposes to carry out a structure-activity relationship study using these three compounds as lead analogues. The synthesis of compounds listed in Series I-IX and their evaluation as inhibitors of TS catalytic activity and tumor cell growth in culture will be carried out. In addition, studies of the effect of the analogues on the RNA binding activity of TS protein, on the ability of TS protein to regulate (repress) TS mRNA translation in vitro, and on the effect of these compounds on TS expression in human colon cancer cells are proposed. The biological evaluation will be carried out by Dr. Chu. The most promising of these compounds will be submitted to the National Cancer Institute for evaluation in their preclinical tumor panel. This work is expected to afford potent TS inhibitors that do not induce TS protein, and will allow delineation of the optimal structural requirements for potent TS inhibitors that do not induce TS synthesis. The long term goals of the study are to allow delineation of the molecular mechanism of binding of ligand-bound TS complexes with TS mRNA, and to provide compounds that can be used alone or in combination with other drugs to overcome the problem of resistance arising from elevation of TS protein levels due to disruption of the normal mechanism of TS mRNA translational autoregulation.
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