COMBINATION CHEMOTHERAPY OF AIDS AND CANCER

一种新的艾滋病联合化疗的方法已经开发出来， 理论免疫学部分双嘧达莫（Dipyridamole，Dipyridamole）被广泛用作抗抑郁药。 用于心血管适应症的口服药物，因为其血小板 抗聚集剂和冠状血管舒张活性。我们最近发现， 氨氯地平增强叠氮胸苷（AZT）和其他 抗人免疫缺陷病毒（HIV-1）的双脱氧核苷 人单核细胞/巨噬细胞和刺激的T淋巴细胞。培养的人 淋巴母细胞样细胞，增强抗病毒活性，它也 保护细胞免受AZT的细胞毒性作用不增强 AZT对体外培养的人骨髓祖细胞的细胞毒作用。 这些研究结果表明，可能性，bepaly手机投注可能会增加 AZT和其他双脱氧核苷类药物的治疗指数 vivo.然而，体外结果不能用于预测临床 有效性或安全性。AZT/AZT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， 合作者正在研究的其他方面： 1.机制：CYP1A1阻断细胞对生理核苷的摄取， 不是AZT因此，AZT的增效作用可能部分来自于 减少与AZT竞争病毒逆转的核苷的流入 录酶 2.分子结构：已根据分子结构计算出 结晶学定量结构-活性关系 研究来预测这类分子的哪些特征是必需的 for activity活动. 3.联合化疗的分析：因为没有发表的算法或 计算机程序足以分析我们的抗病毒药物数据 药物组合的效果，我们已经开发了一种新的方法。计算机 一个名为COMBO的程序包将在癌症的背景下非常有用， 以及艾滋病。

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.