Dipyridamole potentiates the inhibition by 3'-azido-3'-deoxythymidine and other dideoxynucleosides of human immunodeficiency virus replication in monocyte-macrophages.

Abstract

Dipyridamole (DPM) is commonly used as a coronary vasodilator and inhibitor of platelet aggregation in the treatment of cardiovascular diseases. We report here that DPM potentiates the inhibitory effects of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine against human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages. At the same concentrations, DPM does not potentiate the toxic effects of AZT on these cells or on human bone marrow (granulocytemonocyte) progenitor cells. Since monocyte-macrophage lineage cells appear to be the major reservoir for HIV-1 in vivo, these finding suggest the possibility of using DPM or its analogues in combination chemotherapy of HIV infections.Dipyridamole (DPM; Persantine) is widely used as an oral agent in the treatment of cardiovascular diseases because of its platelet antiaggregant and vasodilator activities (1). At pharmacologic concentrations it has several different mechanisms of action (1,2). The best-studied to date is an inhibitory effect on carrier-mediated transport of nucleosides across cell membranes (3, 4). Through this mechanism, DPM affects primarily the "salvage" pathways for nucleotide production. Hence, it has been studied for cancer chemotherapy in combination with inhibitors of de novo nucleotide synthesis (5-8). We report here that DPM potentiates the inhibitory effects of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) against human immunodeficiency virus type 1 (HIV-1) in cultured human monocytemacrophages. AZT is currently accepted therapy for acquired immunodeficiency syndrome (AIDS); ddC is being used in clinical trials, both as a single agent and in alternation with AZT (9-13). These dideoxynucleosides (ddNs) appear to act principally as inhibitors of the viral reverse transcriptase (9-11). MATERIALS AND METHODS 3842The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Dipyridamole Potentiates the Activity of Various Acyclic Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus

“…DPM has been reported to potentiate the antiviral effects of AZT and ddC in HIV-infected human M/M in vitro (Szebeni et a/., 1989). It was also demonstrated that DPM decreases the cellular uptake of dThd, while it has no effect on the uptake of AZT (Betageri et al, 1990).…”

“…DPM has been studied in cancer chemotherapy in combination with inhibitors of the de novo pathway of nucleotide synthesis, and has been reported to potentiate the cytostatic effect of some antimetabolites (Fischer et el., 1984;Nelson and Drake, 1984;Chan and Howell, 1985). Recently, DPM was also shown to enhance the inhibitory effects of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) on human immunodeficiency virus type 1 (HIV-1) infection in vitro in human monocyte-derived macrophages (M/M) and T-Iymphocytes (Szebeni et al, 1989;Betageri et al, 1990;Patel et al, 1991).…”

Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro.

“…Although the source(s) and mechanism for this activity remain A portion of these results was presented at the 2nd National Conference on Human Retroviruses and Related Infections sponsored by the American Society for Microbiology in Washington, D.C. on 29 January through 2 February 1995 and the Keysone Symposia on Molecular and Cellular Biology, HIV Pathogenesis in Keystone, CO on [17][18][19][20][21][22][23] April poorly understood, aggregation of HIV-1 by large molecular weight molecules (mucins, etc.) in the saliva has been implicated (8,10,11) and is consistent with the HIV-1 particle aggregation and entrapment by saliva observed ultrastructurally on small pore filters (12,13).…”

Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Combination in Human Immunodeficiency Virus Infected Lymphoblastoid Cells

“…* P < 0.005 compared to uninfected H9 cells ** P < 0.001 compared to uninfected H9 cells dNTP pools of GEM,H9, The dNTP pools of GEM, H9, and HIV-infected H9 cells (Koshida et al, 1989a), AZT and castanospermine (Johnson et aI., 1989), AZT and 9-(2-phosphonylmethoxyethyl)-adenine (Smith et al, 1989), and AZT and dipyridamole (Szebeni et et., 1989). We also showed the combination of AZT and FLT to be synergistic against HIV replication in cell culture (Harmenberg et al, 1990a).…”