TY - JOUR
T1 - Stimulation of 5-fluorouracil metabolic activation by interferon-α in human colon carcinoma cells
AU - Schwartz, Edward L.
AU - Hoffman, Mark
AU - O'Connor, Carolyn J.
AU - Wadler, Scott
N1 - Funding Information:
The fluorinated pyrimidine, 5-fluorouracil (FUra 1, is the most commonly employed agent, alone or in combination with other drugs, for the treatment of advanced colorectal carcinoma. As a single agent, FUra has only modest anticancer effects; however, in combination with biochemical modulating agents such as the reduced folate, leucovorin, or the aspartate transcarbamylase inhibitor, N-(phosphonacetyl)-L-aspartate, the efficacy of FUra is markedly enhanced, both in vitro and clinically (1,2). Recombinant human interferons have also been shown to synergistically enhance the cytotoxic effects of FUra in vitrg (3-71, and in clinical trials in patients with advanced colorectal carcinoma, recombinant alfa-2a-IFN (IFNu) employed in combination with FUra resulted in objective clinical response rates higher than ’ Supported by grants from the American Cancer Society (CH-4791, the Mathers Foundation, and Cancer Center Support Grant P30 CA13330 from the National Cancer Institute. Dr. Wadler is a recipient of an American Cancer Society Career Development Award.
PY - 1992/2/14
Y1 - 1992/2/14
N2 - Interferon-α (IFNα) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFNα 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, IFNα 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 IFNα did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFNα also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFNα on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.
AB - Interferon-α (IFNα) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFNα 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, IFNα 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 IFNα did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFNα also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFNα on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.
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U2 - 10.1016/0006-291X(92)91863-L
DO - 10.1016/0006-291X(92)91863-L
M3 - Article
C2 - 1540167
AN - SCOPUS:0026600296
SN - 0006-291X
VL - 182
SP - 1232
EP - 1239
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -
