Capping of bcr-abl antisense oligonucleotides enhances antiproliferative activity against chronic myeloid leukemia cell lines.
Leukemia due to a chromosomal translocation offers an attractive model for the design and testing of antisense agents because the sequence at the translocation junction is unique to the leukemic cell population. Chronic myeloid leukemia is the most common such translocation-induced leukemia. We have found antisense phosphodiester oligonucleotides directed at the bcr-abl junction to be ineffective in inhibiting the growth of CML cell lines. Therefore, we have investigated the effects produced by certain structural modifications of bcr-abl antisense oligonucleotides. For assay purposes we used K562 cells which have the bcr exon 3/abl exon 2 junction and BV173 cells which have the bcr exon 2/abl exon 2 junction. We have found that 5'-capping with a dimethoxytrityl group and 3'-capping with an amino-2-hydroxypropyl group confer antiproliferative activity. The enhancement of activity by capping appears at least partly attributable to exonuclease resistance since stability in serum-containing medium is increased.
Thomas
M
M
Department of Medicine, University of Rochester School of Medicine, New York 14642.
Kosciolek
B
B
Wang
N
N
Rowley
P
P
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003470:Culture Media; D016895:Culture Media, Serum-Free; D005091:Exons; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D016313:Genes, abl; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009857:Oncogenes; D014407:Tumor Cells, Cultured
D003470:Culture Media; D016895:Culture Media, Serum-Free; D016376:Oligonucleotides, Antisense; D016044:Fusion Proteins, bcr-abl