Abstract
The molecular effect of the Philadelphia translocation typical of over 90% of chronic myeloid leukaemia (CML) patients is to create a novel hybrid gene, bcr-abl. The mRNA transcript of this CML-specific gene has only 2 alternative sequences, designated b3a2 and b2a2. Short oligodeoxynucleotide (ODN) sequences complementary (or antisense) to the bcr-abl junction may have potential as leukaemia-specific therapy. However, the studies on ODN targeting bcr-abl reported so far have used ODN linked by either phosphodiester or phosphorothionate linkages. Both of these ODN structures have drawbacks as potential therapeutic agents (nuclease sensitivity, non-specific effects). In contrast, ODN linked by a mixture of methylphosphonate and conventional linkages can mediate cleavage of bcr-abl mRNA target in a sequence-specific fashion, unlike conventionally linked ODN. Poor ODN uptake into intact cells remains a central difficulty for all ODN structures. Several strategies to improve cellular uptake of ODN are under current investigation.
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