Document 0973
 DOCN  M95A0973
 TI    Drug synergism by nucleoside analog drugs against HIV-RT based on
       multiple inhibitor kinetics (Meeting abstract).
 DT    9510
 AU    Periclou AP; Solorzano MM; Avramis VI; Div. of Hematology, USC School of
       Medicine, Los Angeles, CA 90027
 SO    Proc Annu Meet Am Assoc Cancer Res; 36:A1720 1995. Unique Identifier :
       AIDSLINE ICDB/95609495
 AB    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.
 DE    Antiviral Agents/*PHARMACOLOGY  Cell Line  Deoxyadenine
       Nucleotides/*PHARMACOLOGY  Drug Synergism  Human  Reverse
       Transcriptase/*ANTAGONISTS & INHIB  T-Lymphocytes  Thymine
       Nucleotides/*PHARMACOLOGY  Zidovudine/*ANALOGS &
       DERIVATIVES/PHARMACOLOGY  MEETING ABSTRACT

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