COMBINATION THERAPY FOR CANCER AND AIDS

一项偶然的发现引导我们开发了一种新的“调制”组合 艾滋病毒感染的治疗。潘生丁(DPM；Persantin)是一种应用广泛的 廉价的心血管药物，也是一种有效的核苷抑制剂 运输。我们发现DPM增强了AZT抗HIV-1的活性 在培养的人单核/巨噬细胞和刺激的T细胞中。在人类中 T淋巴母细胞(CEM-SS)，DPM增强抗HIV活性和 同时保护细胞免受AZT的伤害。DPM不会增强 用CFU-GM法检测AZT对人骨髓祖细胞的细胞毒作用 综上所述，这些发现表明DPM可能会增加 AZT体内治疗指数和/或降低抗病毒药物成本 心理治疗。我们正在与其他人合作进行I期和Il期临床 AZT/DPM联合试验。我们小组正在研究的几个方面 包括： 1.作用机制：DPM阻断细胞的生理性摄取 核苷，但不包括AZT和ddC。AZT(和ddC)的增强作用可以 因此，部分原因是核苷类物质流入减少 与AZT争夺病毒逆转录酶。 2.分子结构：根据结晶学的发现，我们计算了 DPM的构象结构。定量结构-活性 然后进行关系(3D-QSAR)分析以预测哪些特征 核苷转运抑制分子的活性是必需的。 3.分子生物学：我们正在努力克隆平衡核苷 转运蛋白，DPM的分子靶标，但到目前为止还没有成功。 4.临床试验：在Henry Jackson进行的AZT/DPM的小型临床试验 基金会(与我们的团队和临床部合作 ，约翰·霍普金斯大学)达到第一阶段最大耐受量目标 测定方法和药代动力学特征。第二阶段协议是 正在审查中。 5.联合治疗的一般分析：没有已发表的算法或 计算机程序包足以分析抗病毒药物的数据 组合(包括我们自己的实验)。因此，我们开发了一种 新方法。新的概念和计算机程序包(COMBO)是 在NIH和其他地方与其他组织合作使用 癌症和艾滋病治疗的数据分析和设计实验。 部分由国立卫生研究院针对艾滋病的校内艾滋病项目的赠款支持 抗病毒药物计划。

A serendipitous finding led us to develop a novel "modulatory" combination therapy for HIV infection. Dipyridamole (DPM; Persantin), a widely used, inexpensive cardiovascular agent, is also a potent inhibitor of nucleoside transport. We found that DPM potentiates the activity of AzT against HIV-1 in cultured human monocyte/macrophages and stimulated T-cells. In human T-lymphoblastoid cells (CEM-SS), DPM potentiates the anti-HIV activity and simultaneously protects the cells against AZT. DPM does not potentiate AZT's cytotoxicity for human bone marrow progenitors in the CFU-GM assay. Taken together, these findings suggested that DPM might increase the therapeutic index of AZT in vivo and/or decrease the cost of antiviral therapy. We are collaborating with others on phase I and phase Il clinical trials of the AZT/DPM combination. Aspects under study by our group include: 1. Mechanism of action: DPM blocks cellular uptake of physiological nucleosides but not of AZT and ddC. The potentiation of AZT (and ddC) may thus result, in part, from decreased influx of the nucleosides that compete with AZT for viral reverse transcriptase. 2. Molecular structure: Based on crystallographic findings, we computed conformer structures for DPM. Quantitative structure-activity relationships (3D-QSAR) analyses were then done to predict which features of nucleoside transport-inhibiting molecules are required for activity. 3. Molecular biology: We are trying to clone the equilibrative nucleoside transporter, a molecular target for DPM, but so far without success. 4. Clinical trials: A small clinical trial of AZT/DPM at the Henry Jackson Foundation (in collaboration with our group and the Dept of Clinical Pharm., Johns Hopkins U.) met phase I goals of maximum tolerated dose determination and pharmacokinetic characterization. A phase II protocol is under review. 5. General analysis of combination therapy: No published algorithm or computer package was adequate for analysis of data on antiviral drug combinations (including our own experiments). Hence,we have developed a new approach. The new concepts and computer program package (COMBO) are being used in collaboration with other groups at NIH and elsewhere to analyze data and design experiments on therapy of cancer and AIDS. Supported in part by a grant from the NIH Intramural AIDS Targeted Antivirals Program.