Didanosine (2',3'-Dideoxyinosine, ddI) is one of the principal antiretroviral drugs available for patients infected with the Human Immunodeficiency Virus. This drug, however, manifest significant clinical side effects, which differ from the spectrum of toxicity of other nucleoside analogues such as Zidovudine. It was our aim to examine the possible intracellular targets for the toxicity associated with ddI in uninfected cells. In 72 hrs growth inhibition assays, ddI was not toxic to U937 cells (IC50 greater than 500 micromolar). Cells incubated with 10 micromolar H3-ddI showed radioactive material associated with both RNA (alkali-stable) and DNA (alkali-labile) fractions within a period of 2 hrs. The HPLC analysis of the intracellular soluble metabolites of ddI evidenced the formation of ddATP under these conditions. On the other hand, the chronic treatment of U937 cells with ddI takes about 16 days to see a significant delay in growth. The exposure to 100 micromolar ddI for 16 days resulted in a 2-fold increase in the production of lactic acid, suggesting an effect on mitochondrial functions. Experiments are in progress to identify the species incorporated into the nucleic acids and to evaluate the direct effects of ddI on mitochondria. These results are relevant to understand the biological activities of ddI or its analogues, and the interactions that could affect various drug combination strategies involving ddI.

Cell Division/DRUG EFFECTS Cell Line Chromatography, High Pressure Liquid Drug Interactions Human Thymidine/ANALOGS & DERIVATIVES/*PHARMACOLOGY Thymidine Kinase/ANTAGONISTS & INHIB Zidovudine/METABOLISM/*PHARMACOKINETICS/TOXICITY ABSTRACT

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