Human immunodeficiency virus type 1 induces 1-beta-D-arabinofuranosylcytosine resistance in human H9 cell line.
We have found that chronically HIV-1(IIIB)-infected H9 cells showed 21-fold resistance to 1-beta-D-arabinofuranosylcytosine (ARA-C) compared with uninfected H9 cells. In the infected H9 cells, a 37% increase of dCTP pool and a 34% increase of dATP were observed, and no alteration of dTTP and dGTP was observed, compared with the uninfected H9 cells. A marked decrease of ARA-CTP generation was observed in the infected H9 cells after 3-h incubation with 0.1-10 microM ARA-C. The level of deoxycytidine kinase activity with ARA-C as substrate was similar in both the infected and the uninfected cells; however, a 37-fold increase of cytidine deaminase activity was observed in the infected H9 cells. These results indicate that the induction of cytidine deaminase activity by HIV-1(IIIB) infection conferred ARA-C resistance to H9 cells. This conclusion was supported by the observation that a marked reversal of ARA-C resistance in the infected H9 cells occurred after treatment with the inhibitor of cytidine deaminase, 3,4,5,6-tetrahydrouridine. The understanding of these cellular alterations in drug sensitivity may facilitate the development of effective therapeutic strategies against HIV-1-infected cells.
Yusa
K
K
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Oh-hara
T
T
Tsukahara
S
S
Tsuruo
T
T
D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D013767:Tetrahydrouridine / Q000494:pharmacology
D003854:Deoxyribonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D013767:Tetrahydrouridine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase