COMBINATION CHEMOTHERAPY OF AIDS AND CANCER

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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.