COMBINATION CHEMOTHERAPY OF AIDS AND CANCER

一种新的艾滋病联合化疗方法在#年被开发出来 理论免疫学部分。双嘧达莫(DPM)被广泛用作一种 心血管主治口服药因其含有血小板 抗聚集和冠脉血管扩张活性。我们最近发现， DPM增强叠氮胸苷(AZT)和其他 双脱氧核苷在体外抗人类免疫缺陷病毒(HIV-1)的研究 人单核/巨噬细胞和刺激的T淋巴细胞。在培养的人类中 淋巴母细胞，DPM增强了抗病毒活性，它还 保护细胞免受AZT的细胞毒作用。DPM不会增强 AZT对体外培养的人骨髓祖细胞的细胞毒作用 这些发现表明，DPM可能会增加 AZT和其他双脱氧核苷类药物的疗效指标 活着。然而，体外试验结果不能用于临床预测。 有效性或安全性。AZT/DPM已被批准用于艾滋病研究 临床试验组。第一阶段试验正在计划中，与 合作者。正在研究的其他方面： 1.机制：DPM阻断细胞对生理核苷的摄取，但 不是AZT的。因此，AZT的增强作用可能部分是由于 减少与AZT竞争病毒逆转的核苷的流入 转录酶。 2.分子结构：计算了DPM的分子结构 结晶学。定量结构-活性关系正在 研究预测这类分子的哪些特性是必需的 用于活动。 3.联合化疗分析：由于没有已发表的算法或 计算机包足以分析我们关于抗病毒药物的数据 根据药物组合的效果，我们开发了一种新的方法。这台电脑 程序包，称为COMBO，将在癌症的背景下有用，因为 还有艾滋病。

A new approach to combination chemotherapy of AIDS has been developed in the Theoretical Immunology Section. Dipyridamole (DPM) is widely used as an oral agent for cardiovascular indications because of its platelet antiaggregant and coronary vasodilation activities. We recently found that DPM potentiates the activity of azidothymidine (AZT) and other dideoxynucleosides against human immunodeficiency virus (HIV-1) in cultured human monocyte/macrophages and stimulated T-lymphocytes. In cultured human lymphoblastoid cells, DPM potentiates the antiviral activity, and it also protects the cells from AZT's cytotoxic effects. DPM does not potentiate the cytotoxic effect of AZT on human bone marrow progenitor cells in vitro. These findings suggest the possibility that DPM might increase the therapeutic index of AZT and, perhaps, other dideoxynucleoside agents in vivo. However, the in vitro results cannot be used to predict clinical efficacy or safety. AZT/DPM has been approved for study by the AIDS Clinical Trial Group. Phase I trials are being planned, in conjunction with collaborators. Other aspects under study: 1. Mechanism: DPM blocks cellular uptake of physiological nucleosides but not of AZT. The potentiation of AZT may thus result, in part, from decreased influx of the nucleosides that compete with AZT for viral reverse transcriptase. 2. Molecular structure: A structure for DPM has been computed from the crystallography. Quantitative structure-activity relationships are being studied to predict which features of this class of molecules are required for activity. 3. Analysis of combination chemotherapy: Because no published algorithm or computer package was adequate for analysis of our data on the antiviral effect of drug combinations, we have developed a new approach. The computer program package, called COMBO, wilt be useful in the context of cancer as well as AIDS.