Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2115523 | Cancer Letters | 2006 | 8 Pages |
Abstract
Thymidine phosphorylase (TP) regulates intracellular thymidine metabolism and can enhance the anti-tumor effectiveness of 5â²-deoxy-5-fluorouridine (5â²-DFUR) by conversion of the pro-drug 5â²-DFUR to 5-fluorouracil (5-FU) in tumor tissues. 5â²-DFUR is an effective anti-tumor drug in cells expressing high levels of TP. 3â²-Azido 3â²-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 5â²-DFUR. Both the protein level and the activity of TP in U937 cells were elevated for 48 h after exposure to AZT (20, 100 or 300 μM). 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 5â²-DFUR on U937 cells. A TP inhibitor, TPI, abrogated the cytotoxic activity of 5â²-DFUR, and attenuated the combined cytotoxicity of AZT and 5â²-DFUR. These results suggest that AZT enhances the cytotoxic effect of 5â²-DFUR on U937 cells by upregulating TP activity in addition to its inhibition of thymidine kinase (TK) activity and reduction of intracellular dTTP pools.
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Authors
Kengo Tsuneyoshi, Misako Haraguchi, Zhao Hongye, Takenari Gotanda, Tokushi Tachiwada, Tomoyuki Sumizawa, Tatsuhiko Furukawa, Masanori Baba, Shin-ichi Akiyama, Masayuki Nakagawa,