COMBINATION THERAPY FOR CANCER AND AIDS

这个项目是从我们实验室发现一种新的可能性开始的。 艾滋病的“调节性”联合疗法(AZT或ddC加一种 生理核苷进入细胞的运输)。一种这样的抑制剂 是潘生丁，一种常用的心血管药物。经过对……的研究 机制、分子生物学和临床前药理学 AZT和潘生丁联合应用于I期临床 与亨利·杰克逊基金会和约翰斯的合作者进行的试验 霍普金斯大学。在剂量范围方面达到了第一阶段的目标 和临床药理学。一个II期临床方案收到了所有 必要的审批，但由于资金问题和 关键人员的工作变动。 我们目前在联合疗法方面的工作是那些研究的结果。 我们找不到任何已发表的设计和分析方法 关于联合治疗的实验似乎足以完成这项任务。 因此，我们开发了自己的产品。其结果是一组不断增长的新的 概念、算法和计算机程序，嵌入到一个称为 套餐。这项工作普遍适用于治疗实验 癌症和艾滋病，现在构成了这个项目的中心部分，尽管 这只是我们研究组整体努力的一小部分。 使用新的算法和程序进行了设计和分析 苏拉明、肿瘤坏死因子、紫杉醇、 双嘧达莫、AZT、DDI、ddC、CD4-假单胞菌外毒素、HIV蛋白酶 抑制剂和羟基脲等。去年的分析显示 对AZT或DDI与蛋白酶抑制剂KNI-272的组合进行了研究 与H.Mitsuya及其同事(艾滋病研究和人类逆转录病毒 1994年；38：1036)和加洛及其同事(《科学》1994；266：80L)。

This project began with the discovery in our laboratory of a new possible "modulatory" combination therapy for AIDS (AZT or ddC plus an inhibitor of the transport of physiological nucleosides into cells). One such inhibitor is dipyridamole, a commonly used cardiovascular agent. After studies of mechanism, molecular biology, and preclinical pharmacology, the combination of AZT and dipyridamole was carried through Phase I clinical trials with collaborators at the Henry Jackson Foundation and Johns Hopkins University. Phase I goals were met with respect to dose-ranging and clinical pharmacology. A phase II clinical protocol received all necessary approvals but was not carried out because of funding issues and job changes by key personnel. Our current work on combination therapy was an outgrowth of those studies. We could not find any published method for designing and analyzing experiments on combination therapy that appeared adequate to the task. Hence, we have developed our own. The result is a growing set of new concepts, algorithms, and computer programs, embedded in a package called COMBO. That work, which has general application to experiments on therapy of cancer and AIDS, now forms the central portion of this project, albeit a small fraction of overall effort in our research group. We have used the new algorithms and programs to design and analyze experiments on such agents as suramin, tumor necrosis factor, taxol, dipyridamole, AZT, ddI, ddC, CD4-pseudomonas exotoxin, HIV protease inhibitors, and hydroxyurea, among others. Analyses in the last year have been done on combinations of AZT or ddI with protease inhibitor KNI-272 with H. Mitsuya and colleagues (AIDS Research and Human Retroviruses 1994;38:1036) and with Gallo and colleagues (Science 1994;266:8Ol).