Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells.

Abstract

Interferon-alpha (IFN alpha) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFN alpha treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFN alpha produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFN alpha did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFN alpha also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFN alpha on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.

• Authors: E L Schwartz, M Hoffman, C J O'Connor, S Wadler
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 182 Issue 3 Pg. 1232-9 (Feb 14 1992) ISSN: 0006-291X [Print] United States
• PMID: 1540167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Neoplasm
• Interferon alpha-2
• Interferon-alpha
• RNA, Neoplasm
• Recombinant Proteins
• Tritium
• Adenosine
• Fluorouracil
• Thymidine

Topics

• Adenosine (metabolism)
• Biotransformation
• Cell Line
• Colonic Neoplasms
• DNA, Neoplasm (biosynthesis)
• Fluorouracil (metabolism)
• Humans
• Interferon alpha-2
• Interferon-alpha (pharmacology)
• Kinetics
• RNA, Neoplasm (biosynthesis)
• Radioisotope Dilution Technique
• Recombinant Proteins
• Thymidine (metabolism)
• Tritium