EFFECTS OF STEROIDAL ACID AZT CONJUGATES ON HUMAN LYMPHOBLASTIC CEM CELLS: HIV

人类免疫缺陷病毒(HIV)感染的药物治疗 变得越来越复杂。多种治疗性和预防性药物 被用来对抗艾滋病毒感染和随之而来的机会主义 并发症。核苷类似物抗逆转录病毒治疗和 预防性治疗是目前艾滋病毒感染的主要手段。 治疗，但这些药物往往有不良反应，可能导致 减少剂量，停止治疗，甚至需要治疗 由不良反应事件引起的病态反应。齐多夫定(AZT) 核苷类似物逆转录酶抑制剂，具有临床应用价值 艾滋病患者的活动或艾滋病相关情结，但其 毒性，特别是对骨髓的毒性，可能需要剂量 减少、中断治疗。一 提高AZT选择性指数的途径是将 抗病毒核苷为甾体酸载体分子。在 甾体酸-AZT酯共轭形式的假设 糖皮质激素部分将有助于核苷进入细胞 酶解可使AZT恢复到治疗水平 随着时间的推移，从而避免了AZT单磷酸的过度积累 影响宿主细胞DNA合成，导致细胞停滞和细胞 毒性。有可能共轭化合物和/或甾体部分 可与胞浆糖皮质激素结合和释放 受体。这项提议的长期目标是调查 甾体酸-AZT偶联剂的药理作用 培养中的人淋巴母细胞系CEM细胞。拟议的调查是 旨在探索共轭形式，甾体酸的影响 和AZT单独或作为未结合混合物对CEM细胞的细胞抑制作用， 细胞毒性、DNA生物合成、与AP-1复合体的相互作用 转录调节因子，竞争性的全细胞结合到 糖皮质激素受体、糖皮质激素调节酶的诱导 以及长期暴露后类固醇抗药性的发展。 这些实验的成功完成将为深入了解 新型甾体酸-核苷偶联物的设计 宿主细胞毒性。这些代理商可能会有一个重要的未来 替代减量的辅助治疗方法 因出现不良反应而中断治疗

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