Induction of thymidine phosphorylase expression by AZT contributes to enhancement of 5'-DFUR cytotoxicity.
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.
Tsuneyoshi
Kengo
K
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan.
Haraguchi
Misako
M
Hongye
Zhao
Z
Gotanda
Takenari
T
Tachiwada
Tokushi
T
Sumizawa
Tomoyuki
T
Furukawa
Tatsuhiko
T
Baba
Masanori
M
Akiyama
Shin-Ichi
S
Nakagawa
Masayuki
M
D000963:Antimetabolites / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D004357:Drug Synergism; D005467:Floxuridine / Q000633:toxicity*; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D014162:Transfection; D020298:U937 Cells / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
D000963:Antimetabolites; D005467:Floxuridine; D015215:Zidovudine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine