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Institute of Zoology, Bulgarian Academy of Sciences, Sofia 1000, Bulgaria [M. T-A.]; Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany [H. E.]; and Unit of Toxicology and Chemotherapy, German Cancer Research Center, 69120 Heidelberg, Germany [S. M. K., M. C. G., M. R. B.]

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.

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