Induction of thymidine phosphorylase expression by AZT contributes to enhancement of 5′-DFUR cytotoxicity
Autor: | Takenari Gotanda, Kengo Tsuneyoshi, Masanori Baba, Tokushi Tachiwada, Shin-ichi Akiyama, Zhao Hongye, Misako Haraguchi, Masayuki Nakagawa, Tatsuhiko Furukawa, Tomoyuki Sumizawa |
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Rok vydání: | 2006 |
Předmět: |
Cancer Research
Antimetabolites Cell Survival viruses Biology Transfection chemistry.chemical_compound Humans Cytotoxic T cell heterocyclic compounds Thymidine phosphorylase Cytotoxicity Thymidine Phosphorylase U937 cell Myeloid leukemia Drug Synergism U937 Cells Molecular biology Oncology chemistry Thymidine kinase Fluorouracil Floxuridine Thymidine Zidovudine Intracellular |
Zdroj: | Cancer Letters. 244:239-246 |
ISSN: | 0304-3835 |
Popis: | 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 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 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. |
Databáze: | OpenAIRE |
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