Drug synergism by nucleoside analog drugs against HIV-RT based on multiple inhibitor kinetics (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Drug synergism by nucleoside analog drugs against HIV-RT based on multiple inhibitor kinetics (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A1720 1995. Unique Identifier : AIDSLINE ICDB/95609495
Periclou AP; Solorzano MM; Avramis VI; Div. of Hematology, USC School of Medicine, Los Angeles, CA 90027

Abstract: Azidothymidine (AZT) and didanosine (ddI) have been shown to be synergistic against HIV in T-cell lines. We have examined the theoretical kinetics of a single enzyme (HIV-RT) with multiple substrates in the presence of one or more inhibitors. Based on the Michaelis-Menten kinetics of inhibition, the velocity (V) of the RT is a fraction of its Vmax which can become minimal in the presence of either very high inhibitor concentrations or relatively high concentrations of multiple independent competitive inhibitors, such as AZTTP and ddATP. We have examined the cellular anabolite concentrations of AZT and ddI in sensitive and resistant to AZT cell lines. AZTTP is augmented by 60% in Jurkat/0 T-cells (14.2 +/- 2.2 nM) when AZT follows treatment with 1 uM ddI for 2 hours. An even greater increase of AZTTP is detected in Jurkat/AZT-10, a partially resistant to AZT T-cell line. This indicates that the effective concentration of this inhibitor of HIV-RT increased significantly in the presence of the second inhibitor, ddATP. The relative concentrations of ddATP were similar in Jurkat/0 (49.4 +/- 4.5 nM) and Jurkat/AZT-10 (53.9 +/- 3.6 nM) T-cell lines. DdATP cellular levels were not different in both T-cell lines cultured in the presence or absence of 1 uM AZT. Hence, in the presence of both AZTTP and ddATP, AZTTP is increased significantly, whereas ddATP remains unchanged. Hence, HIV-RT can be inhibited more efficiently not only because of the mere presence of both independent inhibitors, but due to the significant increase of one, AZTTP, after the sequential treatment of these drugs.

Keywords: Antiviral Agents/*PHARMACOLOGY Cell Line Deoxyadenine Nucleotides/*PHARMACOLOGY Drug Synergism Human RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB T-Lymphocytes Thymine Nucleotides/*PHARMACOLOGY Zidovudine/*ANALOGS & DERIVATIVES/PHARMACOLOGY ABSTRACT
951030
M95A0967

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