Document 0692
 DOCN  M9650692
 TI    Uptake and distribution of 2',3'-dideoxyinosine and its derivatives in a
       human monocytoid cell line.
 DT    9605
 AU    Vazquez-Padua MA; Mayol N; Lopez M; Department of Anatomy and Cell
       Biology, Universidad Central del; Caribe, School of Medicine, Bayamon,
       Puerto Rico 00960-6032.
 SO    Cell Mol Biol (Noisy-le-grand). 1995;41 Suppl 1:S113-9. Unique
       Identifier : AIDSLINE MED/96171641
 AB    The dideoxynucleoside analogue 2',3'-dideoxyinosine (ddI) has been used
       in the clinic as an alternative drug to zidovudine (AZT) in the
       treatment of patients with the acquired immunodeficiency syndrome
       (AIDS). However, it shows significant and variable toxicity in patients.
       It is known that various dideoxynucleoside analogues can cause the
       termination of the DNA chain following incorporation of the
       corresponding triphosphate metabolite by the polymerases. In the case of
       ddI, the presumed active metabolite is 2',3'-dideoxyadenosine
       5'-triphosphate (ddATP). In order to understand the molecular basis for
       the toxicity of ddI, we evaluated the relationship between the
       intracellular formation of ddATP, its incorporation into cellular DNA
       and the effects on the growth of U937 cells, a human monocytoid cell
       line. Dideoxyinosine was not significantly toxic to U937 cells at
       concentrations as high as 500 microM in a 72 hrs. growth inhibition
       assay. The results of the uptake of 3HddI in this cell line showed a
       proportional increase in total metabolites with increasing
       concentrations of the drug (1-20 microM) after a 24 hrs. exposure.
       Incubation with 10 microM 3HddI resulted in the formation of low levels
       of ddATP within a period of 2 hrs. A significant amount of ddI-derived
       radioactivity was found in both DNA and RNA after exposure to 10 microM
       3HddI for 24 to 72 hrs. However, no evidence of incorporation of ddATP
       into the cellular DNA fraction was obtained in these experimental
       conditions. Therefore, the lack of significant toxicity of ddI to U937
       cells can be explained, at least in part, by its inability to
       incorporate ddATP into its cellular DNA at the doses studied.
 DE    Biological Transport  Biotransformation  Cell Division/DRUG EFFECTS
       Comparative Study  Deoxyadenine Nucleotides/METABOLISM
       Didanosine/*METABOLISM/TOXICITY  DNA Damage  DNA Replication  DNA,
       Neoplasm/METABOLISM  Human  Lymphoma, Large-Cell/PATHOLOGY
       Monocytes/DRUG EFFECTS/*METABOLISM  RNA, Neoplasm/METABOLISM  Support,
       U.S. Gov't, P.H.S.  Tumor Cells, Cultured  Zidovudine/METABOLISM
       JOURNAL ARTICLE

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