Inhibition of Epstein-Barr virus early antigen activation promoted by 12-O-tetradecanoylphorbol-13-acetate by the non-steroidal anti-inflammatory drugs

As part of our screening program for cancer inhibitory agents effective spe cifically in the promotion stage of cancer development, we have evaluated t he possible inhibitory effects of 36 non-steroidal anti-inflammatory drugs (NSAIDs) on the Epstein-Barr virus early antigen (EBV-EA) activation which was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Al l the drugs were observed to inhibit the EBV-EA activation at low doses wit h low toxicity. The two most active anti-tumor promoting agents were the ar ylacetic acid derivatives, etodolac and sulindac. We also report for the fi rst time the activities of 14 new NSAIDs belonging to different classes as potential cancer chemopreventive agents. A structure-activity relationship study showed that among the salicylic acid derivative tested, the oxidation of the thiol group to dithiol derivatives results in the reduction of the activity. Introduction of amino group on the salicylic acid molecules also results in the reduction of activity in the EBV-EA assay. The results are o f great interest in the development of NSAIDs as cancer chemopreventive age nts, which halt cancer progression in multistage carcinogenesis, where succ essive activities are required to evolve into fully-hedged and metastatic c ancer. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.