Cross-resistance of dideoxycytidine-resistant cell lines to azidothymidine

Ram P. Agarwal, Wei Wang, Peggy Yo, Tieran Han, Marilyn Fernandez

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

2',3'-Dideoxycytidine (ddC) and azidothymidine (AZT) inhibit HIV-1 replication and currently are used in AIDS therapy. Long-term use of the drugs is associated with the selection of drug-resistant HIV strains, thus limiting their effectiveness. Another mechanism, associated with their altered metabolism in host cells, also can cause 'cellular' drug resistance. Human lymphocytic H9 cell lines (H9-ddC0.5w and H9-ddC5.0w) selected for ddC resistance by exposure to 0.5 and 5.0 μM ddC were found to be cross-resistant to AZT. Compared with controls, the thymidine kinase (TK) activities in H9-ddC0.5w and H9-ddC5.0w cells were 56.7 and 51.4% (with thymidine as a substrate) and 50.3 and 42% (with AZT as a substrate). Consequently the cellular incorporation of AZT and thymidine (24-hr incubation) also was reduced to 51.3 and 70.0% in H9-ddC0.5w cells and to 12.1 and 17.3% in H9-ddC5.0w cells. A 3-hr incubation with 25 μM AZT and ddC decreased their cellular incorporation to 50.5 and 76.15% in H9-ddC0.5w cells and to 12.95 and 47.8% in H9-ddC5.0w cells compared with H9 cells. Thus, the change in AZT accumulation did not correlate exactly with the decrease in TK activity and far exceeded the effect on ddC accumulation. Evidence is presented that ddC, in addition to deoxycytidine kinase, affected TK1 activity. The involvement of multidrug resistance proteins in the mechanism of the resistance was ruled out by the failure of trifluoperazine and verapamil to alter cellular accumulations of AZT, ddC, daunorubicin, and rhodamine-123. Development of cellular ddC and AZT cross-resistance may affect the therapeutic efficacy of these antiviral agents. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)1603-1608
Number of pages6
JournalBiochemical Pharmacology
Volume58
Issue number10
DOIs
StatePublished - Nov 15 1999
Externally publishedYes

Fingerprint

Zalcitabine
Zidovudine
Cells
Cell Line
Thymidine Kinase
Thymidine
Deoxycytidine Kinase
Pharmaceutical Preparations
P-Glycoproteins
Rhodamine 123
Trifluoperazine
Daunorubicin
Substrates
Verapamil
Drug Resistance
Metabolism
Antiviral Agents
HIV-1
Acquired Immunodeficiency Syndrome
HIV

Keywords

  • 2',3'-Dideoxycytidine
  • Azidothymidine
  • Cellular resistance
  • ddC-AZT cross-resistance
  • Reverse transcriptase inhibitors

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cross-resistance of dideoxycytidine-resistant cell lines to azidothymidine. / Agarwal, Ram P.; Wang, Wei; Yo, Peggy; Han, Tieran; Fernandez, Marilyn.

In: Biochemical Pharmacology, Vol. 58, No. 10, 15.11.1999, p. 1603-1608.

Research output: Contribution to journalArticle

Agarwal, Ram P. ; Wang, Wei ; Yo, Peggy ; Han, Tieran ; Fernandez, Marilyn. / Cross-resistance of dideoxycytidine-resistant cell lines to azidothymidine. In: Biochemical Pharmacology. 1999 ; Vol. 58, No. 10. pp. 1603-1608.
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abstract = "2',3'-Dideoxycytidine (ddC) and azidothymidine (AZT) inhibit HIV-1 replication and currently are used in AIDS therapy. Long-term use of the drugs is associated with the selection of drug-resistant HIV strains, thus limiting their effectiveness. Another mechanism, associated with their altered metabolism in host cells, also can cause 'cellular' drug resistance. Human lymphocytic H9 cell lines (H9-ddC0.5w and H9-ddC5.0w) selected for ddC resistance by exposure to 0.5 and 5.0 μM ddC were found to be cross-resistant to AZT. Compared with controls, the thymidine kinase (TK) activities in H9-ddC0.5w and H9-ddC5.0w cells were 56.7 and 51.4{\%} (with thymidine as a substrate) and 50.3 and 42{\%} (with AZT as a substrate). Consequently the cellular incorporation of AZT and thymidine (24-hr incubation) also was reduced to 51.3 and 70.0{\%} in H9-ddC0.5w cells and to 12.1 and 17.3{\%} in H9-ddC5.0w cells. A 3-hr incubation with 25 μM AZT and ddC decreased their cellular incorporation to 50.5 and 76.15{\%} in H9-ddC0.5w cells and to 12.95 and 47.8{\%} in H9-ddC5.0w cells compared with H9 cells. Thus, the change in AZT accumulation did not correlate exactly with the decrease in TK activity and far exceeded the effect on ddC accumulation. Evidence is presented that ddC, in addition to deoxycytidine kinase, affected TK1 activity. The involvement of multidrug resistance proteins in the mechanism of the resistance was ruled out by the failure of trifluoperazine and verapamil to alter cellular accumulations of AZT, ddC, daunorubicin, and rhodamine-123. Development of cellular ddC and AZT cross-resistance may affect the therapeutic efficacy of these antiviral agents. Copyright (C) 1999 Elsevier Science Inc.",
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AB - 2',3'-Dideoxycytidine (ddC) and azidothymidine (AZT) inhibit HIV-1 replication and currently are used in AIDS therapy. Long-term use of the drugs is associated with the selection of drug-resistant HIV strains, thus limiting their effectiveness. Another mechanism, associated with their altered metabolism in host cells, also can cause 'cellular' drug resistance. Human lymphocytic H9 cell lines (H9-ddC0.5w and H9-ddC5.0w) selected for ddC resistance by exposure to 0.5 and 5.0 μM ddC were found to be cross-resistant to AZT. Compared with controls, the thymidine kinase (TK) activities in H9-ddC0.5w and H9-ddC5.0w cells were 56.7 and 51.4% (with thymidine as a substrate) and 50.3 and 42% (with AZT as a substrate). Consequently the cellular incorporation of AZT and thymidine (24-hr incubation) also was reduced to 51.3 and 70.0% in H9-ddC0.5w cells and to 12.1 and 17.3% in H9-ddC5.0w cells. A 3-hr incubation with 25 μM AZT and ddC decreased their cellular incorporation to 50.5 and 76.15% in H9-ddC0.5w cells and to 12.95 and 47.8% in H9-ddC5.0w cells compared with H9 cells. Thus, the change in AZT accumulation did not correlate exactly with the decrease in TK activity and far exceeded the effect on ddC accumulation. Evidence is presented that ddC, in addition to deoxycytidine kinase, affected TK1 activity. The involvement of multidrug resistance proteins in the mechanism of the resistance was ruled out by the failure of trifluoperazine and verapamil to alter cellular accumulations of AZT, ddC, daunorubicin, and rhodamine-123. Development of cellular ddC and AZT cross-resistance may affect the therapeutic efficacy of these antiviral agents. Copyright (C) 1999 Elsevier Science Inc.

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