Thymidine phosphorylase (TP) regulates intracellular
thymidine metabolism and can enhance the anti-
tumor effectiveness of
5'-deoxy-5-fluorouridine (5'-DFUR) by conversion of the
pro-drug 5'-DFUR to
5-fluorouracil (5-FU) in
tumor tissues.
5'-DFUR is an effective anti-
tumor drug in cells expressing high levels of TP. 3'-Azido 3'-deoxythymidine (AZT) is a
thymidine analog that has been proven useful in the treatment of acquired immunodefiency syndrome (
AIDS). In this study, we found that AZT induces TP expression and enhances the sensitivity of human
myeloid leukemia U937 cells to
5'-DFUR. Both the
protein level and the activity of TP in U937 cells were elevated for 48h after exposure to AZT (20, 100 or 300muM). AZT enhanced TP promoter activity in a dose-dependent manner. AZT also increased TP
mRNA levels in U937 cells as assayed by Real-time reverse-transcription PCR. AZT enhanced the cytotoxic effect of
5'-DFUR on U937 cells. A TP inhibitor, TPI, abrogated the cytotoxic activity of
5'-DFUR, and attenuated the combined cytotoxicity of AZT and
5'-DFUR. These results suggest that AZT enhances the cytotoxic effect of
5'-DFUR on U937 cells by upregulating TP activity in addition to its inhibition of
thymidine kinase (TK) activity and reduction of intracellular
dTTP pools.