Interferon (IFN) increased the cytotoxic actions of 5-fluorouracil (FUra) in human colon carcinoma cells in vitro, and IFNBeta was found to be substantially more active than IFNalpha as a modulating agent. Randomized clinical trials found that IFNBeta + FUra, but not IFNalpha + FUra, increased response rate and survival in colorectal cancer patients when compared to FUra alone. In the previous grant period, a biochemical mechanism by which IFN modulates FUra antitumor activity was identified: the induction of expression by IFN, both in vitro and in vivo, of the enzyme thymidine phosphorylase (TP). TP is the first enzyme for the direct conversion of FUra to one of its active metabolites, FdUMP, and has recently been shown to be identical to the angiogenic factor platelet- derived endothelial cell growth factor (PD-ECGF). TP/PD-ECGF levels have been found to be elevated in human solid tumors compared to corresponding normal mucosa, and to show substantial heterogeneity among different individuals. Based on evidence demonstrating that the level of TP/PD-ECGF expression mediates responsiveness to FUra and contributes to the aggressiveness of solid tumors, the studies proposed for the next grant period will continue to delineate the mechanisms of the regulation of TP/PD-ECGF expression, and further define its role in colon cancer in vitro and in vivo.
The specific aims are to: characterize the role of transcriptional and post-transcriptional mechanisms in the constitutive and IFN-induced regulation of TP/PD-ECGF expression in colon carcinoma cells; test the hypothesis that the level of tumor TP/PD-ECGF activity modulates the part of a multi-center, randomized phase III study of FUra + IFNBeta vs. standard FUra therapy in patients with colorectal cancer, determine if the level of TP/PD-ECGF expression in vivo predicts for response to chemotherapy and length of survival; and design and test nucleoside analogs with increased ability to serve as co-substrates for TP/PD-ECGF, thereby increasing their potential to act as biochemical modulators of the antitumor activity of FUra.
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