Abstract
Antisense oligodeoxyribonucleotides (ODN) targeted against the breakpoint in BCR-ABLmRNA will specifically decrease BCR-ABL mRNA, provided cells are first permeabilised with Streptolysin-O (SL-O). We used 18-mer chimeric methylphosphonodiester: phosphodiester linked (4–9-4) ODN complementary to 9 bases either side of the BCR-ABL junction to purge harvests ex vivo in three CML patients who remained completely Ph positive after multiple chemotherapy courses. After CD34+ cell selection and SL-O permeabilisation, harvests were purged with 20 μM ODN. After purging, all individual CFU-GM colonies grown from the two b3a2 breakpoint cases remained positive for BCR-ABL mRNA. In contrast, all 24 colonies grown from the b2a2 breakpoint case were BCR-ABL mRNA negative. Patients were conditioned with busulphan 16 mg/kg. The initial post-transplant course was uneventful, although the time to return to 0.5 × 109/l neutrophils was slow at 25–51 days. Both chronic phase patients remain in haematological remission at +724 and +610 days, although each has cytogenetic evidence of relapse. The b2a2 accelerated phase patient died of myeloid blast transformation at day +91. The present SL-O-facilitated ODN purging strategy appears to be without significant toxicity, and offers considerable improvements in ODN delivery to the cytosol.
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Clark, R., Grzybowski, J., Broughton, C. et al. Clinical use of streptolysin-O to facilitate antisense oligodeoxyribonucleotide delivery for purging autografts in chronic myeloid leukaemia. Bone Marrow Transplant 23, 1303–1308 (1999). https://doi.org/10.1038/sj.bmt.1701801
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DOI: https://doi.org/10.1038/sj.bmt.1701801