POLYAMINE METABOLISM AND AIDS ASSOCIATED PNEUMONIA

多胺代谢和艾滋病相关肺炎

• 批准号: 3141872
• 负责人: ALLEN B CLARKSON JR
• 金额: $ 14.01万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3141872
• 关键词: AIDS; Pneumocystis; Pneumocystis pneumonia; density gradient ultracentrifugation; difluoromethylornithine; disease /disorder model; enzyme inhibitors; high performance liquid chromatography; laboratory rat; opportunistic infections; ornithine decarboxylase; polyamines; putrescine; respiratory disorder chemotherapy

Treatment for AIDs associated Pneumocystis carinti pneumonia (PCP), one of the most common opportunistic infections, is routinely based on only two drug therapies; pentamidine and a combination of trimethoprim with sulfamethoxazole. Considerable success has been met in clinical trials using an anti- polyamine agent, DL-alpha-difluoromethylornithine (DFMP, eflornithine), to treat PCP in those AIDS patients refractory or intolerant to the standard treatment protocols - increasingly common phenomena. While the addition of DFMO to the list of drugs for PCP is welcome, the efficacy needs improvement if anti-polyamine therapy is to be a first line treatment for PCP. The rational approach to such improvement is through investigations of parasite polyamine metabolism and of the interaction of the parasite with antipolyamine agents. Despite this, there has been no exploration of polyamine metabolism in Pneumocystis carinii nor any work directed at improving antipolyamine therapy for PCP. DFMO is a highly specific inhibitor of ornithine decarboxylase (ODC), key enzyme for the biosynthesis of polyamines (small molecules having multiple essential functions in all cells). Although it is targeted to a specific enzyme, there is no direct evidence that the effect of DFMO against PCP is by inhibition of the enzyme. Since the enzyme exists in the host and is both essential and sensitive to DFMO, there is no explanation for the selective activity against the parasite. This proposal is focused on confirming the mode of action of DFMO against PCP and determining the basis for its selective action. Improvements of antipolyamine therapy will be sought via basic studies of the polyamine metabolism of the parasite and studies of the effect of administration and the timing of administration of various polyamine biosynthesis inhibitors to the host. the biochemical action of DFMO will be tested by bypassing the putative metabolic block with exogenous putrescine. The basis for the selective action of the drug against the parasite will be addressed by determining the parasite target enzyme drug sensitivity, recovery rate of parasite enzyme activity after inhibition, DFMO penetration of the parasite and drug distribution in the host. Basic biochemical investigation will be made to devise means of improving anti--polyamine activity for treatment of PCP. The rat model of PCP will be utilized for a source of parasites and a model of the disease.

治疗艾滋病相关的卡氏肺孢子虫肺炎（PCP），1 最常见的机会性感染，通常只基于 两种药物疗法;喷他脒和甲氧苄啶与 磺胺甲恶唑 在使用抗肿瘤药物的临床试验中取得了相当大的成功。 多胺试剂，DL-α-二氟甲基鸟氨酸（DFMP，依氟鸟氨酸）， 治疗那些艾滋病患者的PCP难治性或不耐受， 标准治疗方案-越来越普遍的现象。而 将DFMO添加到PCP的药物清单中是受欢迎的， 如果抗多胺治疗是一线治疗， 治疗PCP。这种改善的合理方法是通过 寄生虫多胺代谢及其相互作用的研究 用抗多胺剂治疗寄生虫尽管如此， 没有探索卡氏肺孢子虫的多胺代谢， 致力于改善PCP的抗多胺疗法。 DFMO是鸟氨酸脱羧酶（ODC）的高度特异性抑制剂， 多胺生物合成的关键酶（小分子具有 所有细胞中的多种基本功能）。虽然它是针对一个 具体的酶，没有直接证据表明DFMO的效果 对付五氯苯酚的方法是抑制这种酶。由于酶存在于 对于DFMO来说，主机是必不可少的，也是敏感的， 对寄生虫的选择性活性的解释。 本提案的重点是确定DFMO的行动方式 并确定其选择性行动的依据。 抗多胺治疗的改进将通过基础研究来寻求 的多胺代谢的寄生虫和研究的影响， 给药和各种多胺的给药时间 生物合成抑制剂。 DFMO的生化作用将通过绕过假定的 外源性腐胺代谢阻断。选择的基础 药物对寄生虫的作用将通过确定 寄生虫靶酶药物敏感性、寄生虫回收率 抑制后的酶活性，DFMO对寄生虫的渗透， 药物在宿主体内的分布。基本的生化调查将是 设计提高抗多胺活性的方法， 的PCP。PCP大鼠模型将用作寄生虫来源 和疾病的模型。