We recently developed a new """"""""modulatory"""""""" combination therapy for AIDS. Dipyridamole (DPM; Persantin) , a potent inhibitor of nucleoside transport, is widely used for cardiovascular indications. We found that DPM potentiates the activity of azidothymidine (AZT) against human immunodeficiency virus (HIV-1) in cultured human monocyte/macrophages and stimulated T-cells. In cultured human T-lymphoblastoid cells, DPM potentiates the antiviral activity and simultaneously protects the cells from AZT's cytotoxicity. DPM does not potentiate AZT's cytotoxic effect on human bone marrow progenitor cells in vitro. Taken together, these findings suggest that DPM may increase the therapeutic index of AZT in vivo. We are currently collaborating with two other institutions on clinical trials of the AZT/DPM combination. Other aspects under study include: 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 (3D-QSAR) are being studied to predict which features of nucleoside transport-inhibiting molecules are required for activity. 3. Molecular biology: Methods based on polymerase chain reaction are being used to clone the nucleoside transport protein, a major target for DPM. 4. Analysis of combination therapy: Because no published algorithm or computer package was adequate for analysis of our data on antiviral drug combinations, we have developed a new approach. The new concepts and prototype computer program package (COMBO), will be useful in the context of cancer as well as AIDS.
