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  • Title: Interaction of gamma interferon and 5-fluorouracil in the H630 human colon carcinoma cell line.
    Author: Chu E, Zinn S, Boarman D, Allegra CJ.
    Journal: Cancer Res; 1990 Sep 15; 50(18):5834-40. PubMed ID: 1697502.
    Abstract:
    The antiproliferative effects and pharmacological interactions of 5-fluorouracil (5-FU) in combination with gamma interferon (IFN-gamma) were determined against the human colon carcinoma H630 cell line in vitro. H630 was 9-fold more resistant to 5-FU, as compared to a relatively sensitive human colon line (C1). IFN-gamma showed modest antiproliferative activity against the H630 line, with a 50% inhibitory concentration of 440 units/ml. Simultaneous treatment of H630 with subinhibitory concentrations of IFN-gamma and 5-FU produced a significant enhancement of the 5-FU-associated growth inhibition. The growth-inhibitory activity of the combination against H630 was prevented by the addition of 20 microM thymidine. Thymidylate synthase (TS) activity was measured by both the 5-fluoro-2'-deoxyuridine-5'-monophosphate binding and catalytic assays, using cytosolic extracts. A 24-h exposure to 1 microM 5-FU in the H630 line resulted in a 3.1-fold increase in the total amount of TS, while in the 5-FU/IFN-gamma-treated cells TS remained unchanged from non-drug-treated control levels. Moreover, we found that free thymidylate synthase in the 5-FU/IFN-gamma-treated cells was significantly decreased, as compared to the cells treated with 5-FU alone. Incorporation of 5-FU into both the RNA and DNA fractions did not change with the addition of IFN-gamma. Accumulation of the fluoropyrimidine metabolites 5-fluoro-2'-deoxyuridine-5'-monophosphate and 5-fluorouridine-5'-triphosphate remained the same for 5-FU alone and the combination treatment. These findings suggest that acute TS induction by 5-FU may provide an important mechanism by which human colon carcinoma cells express decreased sensitivity to 5-FU and that IFN-gamma can reverse the development of resistance to 5-FU in the H630 line by inhibiting the overexpression of TS that results from 5-FU exposure. These studies contribute to a growing understanding of the complex interaction between 5-FU and IFN-gamma.
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