Jung-Chung Lin

Novel acyclic adenosine analogs inhibit Epstein-Barr virus replication.

The effect of three new acyclic adenosine analogs, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], on Epstein-Barr virus (EBV) replication was studied. Both (S)-HPMPA and PMEA but not (S)-DHPA effectively inhibited EBV DNA replication in virus-producer P3HR-1 cells and in latently infected Raji cells superinfected with P3HR-1 virus, as determined by cRNA-DNA hybridization and density gradient centrifugation. The 50% effective doses for inhibiting virus replication were 0.08 and 1.1 microM for (S)-HPMPA and PMEA, respectively. Both drugs were cytostatic but not cytotoxic to the cells at a concentration as high as 100 microM. These results indicate that (S)-HPMPA and PMEA are potent and selective anti-EBV agents in vitro.

Antioxidant-sensitive regulation of inflammatory-response genes in Kaposi's sarcoma cells.

Kaposis sarcoma (KS) is a multifocal vascular lesion characterized by abnormal proliferation of endothelial-like KS cells linked to a pronounced leukocyte infiltration. KS lesions contain novel herpes-like DNA sequences, KSHV, hypothesized to originate from the viral pathogen for KS. Using cultured KS cells that retain the KSHV sequences, diverse signals, including tumor necrosis factor alpha, interleukin (IL) 1 beta, polyinosinic acid/polycytidylic acid and lipopolysaccharide, induced the expression of the cytokine IL-6 and cellular adhesion molecules involved in leukocyte recruitment, including vascular adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). The thiol-antioxidant pyrrolidine dithiocarbamate (PDTC) selectively inhibited > 90% of the activation of nuclear factor kappa B-like DNA binding activity in KS cells. PDTC also reduced by > 85% induced levels of VCAM-1 and IL-6 at the mRNA, protein, and functional levels in KS cells. In contrast, PDTC did not inhibit the induced expression of either ICAM-1 or E-selectin. These studies show that PDTC differentially modulates the expression of inflammatory response genes in KS cells that contain KSHV, suggesting that reduction-oxidation-sensitive events are involved in the regulation of these genes. These studies also suggest that thiol-antioxidants such as PDTC may play a potentially therapeutic role in the treatment of KS by preventing induction of specific inflammatory response genes that may be involved in the pathogenesis of KS.