CELLULAR INTERACTIONS OF 5 FLUOROURACIL AND INTERFERON

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date5/6/942/28/02

ASJC

  • Oncology
  • Cancer Research
  • Virology
  • Cell Biology

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