In vitro Toxicity of 2′,3′-Dideoxy-3′-Thiacytidine (BCH189/3TC), a New Synthetic Anti-HIV-1 Nucleoside

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Abstract
2′,3′-Dideoxy-3′-thiacytidine (BCH189 or 3TC, IAF BioChem International Inc., Montreal, Canada) is a new synthetic anti-HIV-1 dideoxynucleoside with a sulphur atom in the heterocycle ring. Preclinical studies showed that this compound at 5–10 μM displays potent anti-retroviral activity in vitro against HIV-1 infected T (H9 and MT4) and monocyte/macrophage (U937) cell lines, associated with low acute and chronic myelotoxicity in animals. The present study evaluates the in vitro toxicity of BCH189 in comparison with 3′-azido-2′,3′-dideoxythymidine (AZT) on peripheral blood lymphocytes (PBL) from normal subjects and asymptomatic HIV-1 seropositive patients. BCH189 and AZT were used at concentrations ranging from 0.01 to 50 μM, and their action was analysed by: (1) proliferation assay using two activation pathways (concanavalin A and anti-CD3 monoclonal antibody), (2) natural killer (NK) activity, and (3) IL2 receptor (CD25) expression after stimulation with concanavalin A (ConA). Exposure of PBL for 72 h to the two drugs resulted in decreased DNA synthesis only in cells treated with AZT. In particular, BCH189 did not modify significantly cellular proliferation, while a significant inhibition of PBL from normal subjects and HIV-1 positive patients, was observed at AZT concentrations ranging between 5 to 50 μM. Both 2′,3′-dideoxy-3′-thiacytidine (BCH189) and AZT had no effect on NK cytolytic activity. BCH189, at various doses, did not interfere with IL2 receptor (CD25) expression on CD3 positive cells, while AZT, only at very high concentration (50μM), caused a decrease in the number of CD25 positive cells. These studies suggest that BCH189 is less toxic in vitro to lymphocytes than AZT and further support its use in clinical trials on HIV-1 infected subjects as a good alternative to AZT.