An antisense Bcr-Abl phosphodiester-tailed methylphosphonate oligonucleotide reduces the growth of chronic myeloid leukaemia patient cells by a non-antisense mechanism.
The specificity of antisense oligonucleotides targeted to the mRNA breakpoint 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 we designed and tested a methylphosphonate oligonucleotide with an attached 3' soluble phosphodiester tail. Growth of chronic myeloid leukaemia (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 moderately affected or not affected. Bcr-Abl protein studies in combination with growth-determination experiments indicated that the antisense methylphosphonate Bcr-Abl oligonucleotide tested is a potent inhibitor of the growth of CML cells but works in a non-antisense manner.
Smetsers
T F
TF
Department of Haematology, University Hospital St Radboud, Nijmegen, The Netherlands.
Linders
E H
EH
van de Locht
L T
LT
de Witte
T M
TM
Mensink
E J
EJ
D017209:Apoptosis; D002455:Cell Division; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C021992:dideoxyribonucleoside methylphosphonates; D016044:Fusion Proteins, bcr-abl