Differential regulation of telomerase activity in normal and tumor cells provides a rationale for the design of new classes of telomerase inhibitors. The telomerase enzyme complex presents multiple potential sites for the development of inhibitors. GRN163L, a telomerase enzyme antagonist, is a lipid-modified 13-mer oligonucleotide N3V ! P5V -thiophosphoramidate, complementary to the template region of telomerase RNA (hTR). We evaluated both the in vitro and in vivo effects of GRN163L using A549-luciferase (A549-Luc) human lung cancer cells expressing a luciferase reporter. GRN163L (1 Mmol/L) effectively inhibits telomerase activity of A549-Luc cells, resulting in progressive telomere shortening. GRN163L treatment also reduces colony formation in soft agar assays. Surprisingly, after only 1 week of treatment with GRN163L, A549-Luc cells were unable to form robust colonies in the clonal efficiency assay, whereas the mismatch control compound had no effect. Finally, we show that in vivo treatment with GRN163L is effective in preventing lung metastases in xenograft animal models. These in vitro and in vivo data support the development of GRN163L as a therapeutic for the treatment of cancer. (Cancer Res 2005; 65(17): 7866-73)
In spite of unknown etiology, it is now accepted that reactive oxygen species (ROS) produced by neutrophils may be related to the pathogenesis of Behçet's Disease (BD). The objective was to investigate whether increased production of ROS may affect erythrocyte oxidant/antioxidant system in patients with BD. The levels of malondialdehyde (MDA), one of the end products of lipid peroxidation, in plasma and erythrocyte, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), antioxidant enzymes, in erythrocyte, also C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured in 22 patients in active stage of the disease and also in 30 healthy controls. Increased CRP, ESR, and MDA levels in plasma and erythrocyte and increased SOD but decreased GSH-Px activities in erythrocytes were observed in the patients, when compared to the controls. In addition, significantly positive correlations between plasma and erythrocyte MDA levels, and erythrocyte MDA-CRP, MDA-ESR, MDA-SOD, SOD-ESR and SOD-CRP levels, but negative correlation between plasma MDA and erythrocyte GSH-Px, were found in BD patients. It may be suggested that increased production of ROS in BD, as reflected by higher plasma and erythrocyte MDA levels, may impair erythrocyte membrane integrity and also may lead to the alterations in the erythrocyte antioxidant defense system, as reflected by higher SOD and lower GSH-Px activities in erythrocytes.
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