Document 0729
 DOCN  M9650729
 TI    Intracellular activation and cytotoxicity of three different
       combinations of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine.
 DT    9605
 AU    Palmer S; Cox S; Virology Department, Swedish Institute for Infectious
       Disease; Control, Karolinska Institute, Stockholm, Sweden.
 SO    AIDS Res Hum Retroviruses. 1995 Oct;11(10):1227-33. Unique Identifier :
       AIDSLINE MED/96157211
 AB    We measured the intracellular activation and cytotoxicity of
       3'-azido-3'-deoxythymidine (zidovudine, ZDV) and 2',3'-dideoxyinosine
       (ddI) when combined at three different clinically relevant combinations
       of 1:1, 1:10, and 10:1 (ZDV:ddI). The activation of ddI to ddA-TP was
       increased in all three combinations with ZDV, compared to ddI alone. A
       maximum twofold increase in ddA-TP was observed, which could not be
       further increased by raising the concentration of ZDV in the
       combination. On the other hand, the concentration of ZDV in the
       combination could be reduced to one-tenth while retaining increased
       activation of ddI. We also examined the cytotoxicity of these
       combinations in CEM cells, phytohemagglutinin (PHA)-stimulated and
       resting human peripheral blood mononuclear cells (PBMCs). CEM cells were
       the least sensitive overall to the drugs. ZDV showed greater
       cytotoxicity in stimulated PBMCs than resting PBMCs, whereas the reverse
       was true for ddI. This could be explained by the different activation
       pathways of these two drugs. The 1:1 and 10:1 ZDV:ddI combinations
       showed reduced toxicity compared to the separate drugs. These results
       indicate that ZDV and ddI need not necessarily be combined together at a
       ratio of ZDV:ddI of 1:1, but that some alteration in the dosages of ZDV
       or ddI in patients could be possible without loss of the benefits of
       combined ZDV:ddI therapy.
 DE    Antiviral Agents/*TOXICITY  Cell Division/DRUG EFFECTS  Cell Line
       Didanosine/*TOXICITY  Drug Interactions  Human  Reverse Transcriptase
       Inhibitors/*TOXICITY  Support, Non-U.S. Gov't  Thymine
       Nucleotides/METABOLISM  Zidovudine/ANALOGS &
       DERIVATIVES/METABOLISM/*TOXICITY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).