Drug therapy for human immunodeficiency virus (HIV) infections is growing more complex. Multiple therapeutic and prophyclactic agents are being used to combat HIV infection and resultant opportunistic complications. Nucleoside-analog antiretroviral therapy and preventive therapy are the current mainstays of HIV infection treatment but these drugs often have adverse effects which may result in dose reductions, discontinuation of therapy or even a need to treat morbidy resulting from an adverse effect event. Zidovudine (AZT), a nucleoside analogue inhibitor of reverse transcriptase, has clinical activity in patients with AIDS or AIDS-related complex, but its toxicity, particularly on bone marrow, may necessitate dose reductions, interruption of discontinuation of treatment. One approach toward improving the selectivity index of AZT is to link the antiviral nucleoside to a steroidal acid carrier molecule. In the steroidal acid-AZT ester conjugate form it is hypothesized that the gluc ocorticoid moiety would assist entry of the nucleoside into cells where enzymatic hydrolysis would regenerate therapeutic levels of AZT over time, thus avoiding over accumulation of the AZT monophosphate which affects host cell DNA syntheis, induces cytostasis and cell toxicity. It is possible that the conjugate and/or steroidal moiety may undergo binding to and release from the cytosolic glucocorticoid receptor. The long term objective of this proposal is to investigate the pharmacologic effects of the he steroidal acid-AZT conjugated on human lymphoblastic CEM cells in culture. Proposed investigations are designed to explore the impact of the conjugate form, steroidal acids and AZT alone or as unconjugated mixtures on CEM cell cytostasis, cytotoxicity, DNA biosynthesis, interaction with AP-1 complex transcription regulators, competitive whole-cell binding to the glucocorticoid receptor, induction of glucocorticoid regulated enzymes and development of steroid resistance following long term exposure. Successful completion of these experiments will provide insight into the design of novel steroid acid-nucleoside conjugates with minimal host cell toxicity. These agents may ben an important future adjunctive therapeutic approach for us in place of dose reduction or therapy interruption due to onset of adverse reactions
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