AN ANTISENSE BCR-ABL PHOSPHODIESTER-TAILED METHYLPHOSPHONATE OLIGONUCLEOTIDE REDUCES THE GROWTH OF CHRONIC MYELOID-LEUKEMIA PATIENT CELLS BY A NON-ANTISENSE MECHANISM

The specificity of antisense oligonucleotides targeted to the mRNA bre akpoint region of the Bcr-Abl oncogene, found in leukaemic cells from patients with chronic myeloid leukaemia, remains controversial due to non-specific effects. To prevent protein binding of oligonucleotides w e designed and tested a methylphosphonate oligonucleotide with an atta ched 3' soluble phosphodiester tail. Growth of chronic myeloid leukaem ia (CML) cell lines BV173, KCL-22 and cells of CML patients tested was inhibited by the b2a2 type antisense Bcr-Abl oligonucleotide and not with controls. Also the growth of control CD34(+) cells of two healthy donors, control cell lines and cells from AML patients was only moder ately affected or not affected. Bcr-Abl protein studies in combination with growth-determination experiments indicated that the antisense me thylphosphonate Bcr-Abl oligonucleotide tested is a potent inhibitor o f the growth of CML cells but works in a non-antisense manner.