期刊
LEUKEMIA
卷 25, 期 4, 页码 638-647出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.322
关键词
Bcl-2 antisense; gene expression profiling; CLL
资金
- Santaris (Copenhagen, DK)
SPC2996 is a novel locked nucleic acid phosphorothioate antisense molecule targeting the mRNA of the Bcl-2 oncoprotein. We investigated the mechanism of action of SPC2996 and the basis for its clinically observed immunostimulatory effects in chronic lymphocytic leukemia (CLL). Patients with relapsed CLL were treated with a maximum of six doses of SPC2996 (0.2-6 mg/kg) in a multicenter phase I trial. Microarray-based transcriptional profiling of circulating CLL cells was carried out before and after the first infusion of SPC2996 in 18 patients. Statistically significant transcriptomic changes were observed at doses >= 4 mg/kg and occurred as early as 24 h after the first infusion of the oligonucleotide. SPC2996 induced the upregulation of 466 genes including a large number of immune response and apoptotic regulator molecules, which were enriched for Toll-like receptor response genes. Serum measurements confirmed the release of pro-inflammatory cytokines including chemokine (C-C motif) ligand 3 (macrophage inflammatory protein 1 alpha) and tumor necrosis factor-alpha, thereby validating the in vivo transcriptomic data at the protein level. SPC2996 caused a >= 50% reduction of circulating lymphocytes in five of 18 (28%) patients, which was found to be independent of its immunostimulatory and anti-Bcl-2 effects. Leukemia (2011) 25, 638-647; doi:10.1038/leu.2010.322; published online 1 March 2011
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