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ID: 16686.0, MPI für biophysikalische Chemie / Membranbiophysik (Prof. Erwin Neher)
Combination with an antisense oligonucleotide synergistically improves the antileukemic efficacy of erucylphospho-N,N,N- trimethylpropylammonium in chronic myeloid leukemia cell lines
Authors:Konstantinov, S. M.; Georgieva, M. C.; Topashka-Ancheva, M.; Eibl, H.; Berger, M. R.
Date of Publication (YYYY-MM-DD):2002-08
Title of Journal:Molecular Cancer Therapeutics
Issue / Number:10
Start Page:877
End Page:884
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:The aim of this study was to enhance the antileukemic efficacy of the alkylphosphocholine erucylphospho-N,N,N- trimethylpropylammonium (ErPC3) in chronic myeloid leukemia (CML)-derived cell lines by a bcr-directed antisense oligonucleotide (ASO-bcr). The mechanism was substantiated by Western blotting of the BCR-ABL expression level of CML cells, and the efficacy was substantiated by inhibition of colony formation compared with normal hematopoietic cells. The clonogenicity of K-562 cells expressing high levels of p210(BCR-ABL) was inhibited significantly by the ASO-bcr (T/C%, 30; P < 0.05) but not by ErPC3 (T/C%, 70). Combined sequential exposure to ErPC3 and the ASO-bcr, however, inhibited synergistically colony growth (T/C%, 3; P < 0.01). The colony growth of BV-173 cells expressing lower levels of p210(BCR-ABL) than K562 cells was inhibited to a greater extent by the ASO- bcr (T/C%, 15; P < 0.01). AR-230 cells that express high levels of p230(BCR-ABL) showed an intermediate decrease in colony formation in response to the ASO-bcr (T/C%, 20; P < 0.05). BCR- ABL levels of BV-173, CML-T1, and LAMA-84 cells were reduced in response to the ASO-bcr, as evidenced by Western blot. However, K-562 and AR-230 cells showed reduced BCR-ABL expression only after repeated treatment. ErPC3 and the ASO-bcr did not reduce colony formation (CFU-GM) of normal mouse bone marrow cells from long-term bone marrow cell cultures; instead, ErPC3 stimulated colony formation (P < 0.05) and did not induce chromosomal aberrations in mouse bone marrow. In conclusion, the combination of ErPC3 with a suitable antisense oligonucleotide inhibited synergistically colony formation of CML cell lines without damaging normal cells and thus might have a bearing on the purging of autologous hematopoietic transplants in CML patients.
Comment of the Author/Creator:Date: 2002, AUG
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/AG Hans-Jörg Eibl
External Affiliations:German Canc Res Ctr, Unit Toxicol & Chemotherapy, Neuenheimer; Feld 280, D-69120 Heidelberg, Germany; Bulgarian Acad Sci, Inst Zool, Sofia 1000, Bulgaria
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