| Autor: |
Dürig J; Department of Hematology, University Hospital, University of Duisburg-Essen, Essen, Germany. jan.duerig@uk-essen.de, Dührsen U, Klein-Hitpass L, Worm J, Hansen JB, Ørum H, Wissenbach M |
| Jazyk: |
angličtina |
| Zdroj: |
Leukemia [Leukemia] 2011 Apr; Vol. 25 (4), pp. 638-47. Date of Electronic Publication: 2011 Mar 01. |
| DOI: |
10.1038/leu.2010.322 |
| Abstrakt: |
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 1α) and tumor necrosis factor-α, 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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