Arabinosylcytosine downregulates thymidine kinase and induces cross-resistance to zidovudine in T-lymphoid cells.
The aim of this study was to determine molecular mechanism(s) responsible for the reduced thymidine kinase activity (TK) observed earlier in an arabinosylcytosine (araC) resistant lymphoid cell line (H9-araC cells), which was obtained following continuous cultivation of H9 cells in the presence of 0.5 microM araC. Compared to H9 cells, in H9-araC cells TK1 and TK2 gene expressions were reduced to 17.7% and 2.5%, respectively, and the cellular AZT accumulation was diminished to 35.8%. These cells were also found cross-resistant to azidothymidine (>42-fold). There was no significant difference in the expression of MDR1, MRP4 or TK protein. The lack of correlation between the expressions of TK protein and TK1 and TK2 suggests that post-translational factors may also play a role in the reduced TK activity in H9-araC cells. These findings suggest that araC affects TK expression at the genetic level.
Han
Tieran
T
Department of Medicine (M862), PO Box 019132, University of Miami School of Medicine, Room 7084A, RMSB, 1600NW 10 Avenue, Miami, FL 33101, USA.
Fernandez
Marilyn
M
Sarkar
Malancha
M
Agarwal
Ram P
RP
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D019380:Anti-HIV Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004351:Drug Resistance; D013601:T-Lymphocytes; D013937:Thymidine Kinase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015215:Zidovudine / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D019380:Anti-HIV Agents; D003561:Cytarabine; D015215:Zidovudine; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1