The effects of prolonged treatment with zidovudine, lamivudine, and abacavir on a T-lymphoblastoid cell line.
A human T-lymphoblastoid cell line that is resistant to the antiviral activity of zidovudine (ZDV) and moderately resistant to lamivudine (3TC) has been obtained as a result of prolonged treatment with a combination of three nucleoside analogues (NA), ZDV, 3TC, and abacavir (ABV). These cells, called CEM(ZLA), are fully sensitive to ABV. The cellular resistance of the CEM(ZLA) cells to ZDV correlates with significant reductions in thymidine kinase (TK) activity and in the amount of intracellular TK protein. Interestingly, the reduction in TK activity led to impairment of the ability of CEM(ZLA) to accumulate the triphosphate metabolite of ZDV. However, the moderately 3TC-resistant phenotype of CEM(ZLA) cannot be ascribed to a similar reduction in deoxycytidine kinase activity. Compared to the parental CEM cells, CEM(ZLA) cells express a high level of multidrug resistance protein 4 (MRP4), which could reduce the intracellular concentration of 3TC. This study shows that the exposure of cells to a combination of NAs is capable of simultaneously affecting more than one target site to confer resistance and that NAs display differing abilities to select cellular resistance mechanisms.
Turriziani
Ombretta
O
Department of Experimental Medicine-Virology Section, University La Sapienza, Rome, Italy. ombretta.turriziani@uniroma1.it
Pagnotti
Paolo
P
Pierangeli
Alessandra
A
Focher
Federico
F
Baranello
Cinzia
C
Bellomi
Francesca
F
Falasca
Francesca
F
Morgan
Jessica
J
Schuetz
John D
JD
Antonelli
Guido
G
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003842:Deoxycytidine Kinase / Q000378:metabolism; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects; D013937:Thymidine Kinase / Q000378:metabolism; D015215:Zidovudine / Q000627:therapeutic use*; D000099227:Abacavir
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000998:Antiviral Agents; D003842:Deoxycytidine Kinase; D015224:Dideoxynucleosides; D019259:Lamivudine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D013937:Thymidine Kinase; D015215:Zidovudine; D000099227:Abacavir; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human