Antisense strategy: biological utility and prospects in the treatment of hematological malignancies

The use of antisense oligonucleotides for the specific control of cellular genes expression has undergone rapid developments recently. Besides the antisense approach, which usually targets translation initiation or splicing sites, it is also possible to interfere specifically with transcription process through triple helix formation (anti-gene strategy) or through the titration of regulatory proteins (sense and aptamer approaches). Progresses in oligonucleotides chemistry have led to the synthesis of analogs with improved pharmacological properties, while their generation from recombinant vectors in situ has improved oligos deliver to their nuclear or cytoplasmic targets. Hematological malignancies provide an ideal paradigm for the development of antisense therapeutic strategies. Many disease-specific molecular lesions have been identified which provide suitable targets for systemic in vivo administration of oligonucleotides as well as for ex vivo bone marrow purging manipulation. However, oligonucleotides have also been shown to bind to unexpected cellular targets and to induce various unpredictable biological responses as well. In addition, the multi-stage nature of carcinogenesis may indicate that even if successful inhibition of a single gene by oligomer is achieved, it may still be insufficient to induce a major impact on a malignant clone. Thus, much more basic information about both the disease and antisense technology is still required before antisense strategy gains the status of an acceptable therapeutical approach.