Differential alteration of the anti-HIV-1 effect of phosphorothioate oligonucleotide S-dC28 by AZT, interferon-alpha, and dextran sulfate.
The combination of S-dC28 (a phosphorothioate oligodeoxcytidine 28 mer) with AZT, recombinant interferon alpha-A (IFN-alpha A) or dextran sulfate (DS) against replication of human immunodeficiency virus type 1 (HIV-1) were studied in MT4 cells, using both p24 core antigen and reverse transcriptase (RT) assays. Under the standardized conditions, the anti-HIV-1 dose-effect relationships of all test drugs showed sigmoidal curves with the following EC50 values: for the p24 core antigen assay, S-dC28, 0.03 microM; AZT, 0.004 microM; IFN-alpha A, 9.2 U/ml; DS, 0.26 micrograms/ml; for the RT assay, S-dC28, 0.04 microM; AZT, 0.01 microM; IFN-alpha A, 11.6 U/ml; and DS, 0.31 micrograms/ml. A computer software based on the median-effect principle and isobologram techniques were used to quantitatively analyze drug interactions by calculating the combination index (CI) where CI less than 1, = 1, and greater than 1 indicates synergism, additive effect and antagonism, respectively. For p24-ELISA, the interaction of S-dC28 and AZT in combination produced a slight antagonism on HIV-1 replicative inhibition with CI values of 1.29-1.10; for RT assays, at EC50-EC95 levels, the CI values are 1.96-1.11. For p24 core antigen assay, the combination of S-dC28 with IFN-alpha A exhibited a dose-dependent anti-HIV synergism with CI values of 1.15-0.87 at EC75-EC95 levels. The RT assays for the same combination showed a broad synergistic effect with CI values of 0.62-0.60, at EC50-EC95 levels. S-dC28 plus DS showed a nearly additive effect based on both assay methods.(ABSTRACT TRUNCATED AT 250 WORDS)
Chou
T C
TC
Laboratory of Biochemical Pharmacology, Memorial Sloan-Kettering Cancer Center, New York 10021.
Zhu
Q Y
QY
Stein
C A
CA
D002460:Cell Line; D003841:Deoxycytidine / Q000494:pharmacology*; D016264:Dextran Sulfate / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D015458:Leukemia, T-Cell; D011994:Recombinant Proteins; D013601:T-Lymphocytes; D013873:Thionucleotides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000494:pharmacology*
D007370:Interferon Type I; D011994:Recombinant Proteins; D013873:Thionucleotides; D003841:Deoxycytidine; D015215:Zidovudine; D016264:Dextran Sulfate