Antisense therapeutics in chronic myeloid leukaemia: the promise, the progress and the problems

Abstract

DNA sequences which are complementary or 'antisense' to a target mRNA can inhibit expression of that mRNA's protein product. Antisense therapeutics has therefore received attention for inhibiting oncogenes in haematological malignancy, in particular in chronic myeloid leukaemia. However, it is now becoming clear that antisense therapeutics is considerably more problematic than was naively initially assumed. In this article, some of these difficulties are discussed, together with the achievements in CML so far. Considerable further research is required in order to define an optimal antisense therapeutics strategy for clinical use. Leukemia (2000) 14, 347-355.

Curcumin synergistically augments bcr/abl phosphorothioate antisense oligonucleotides to inhibit growth of chronic myelogenous leukemia cells

“…Theoretically, it is one of the ideal therapeutic agents of CML [9,16] . However, they are very poorly soluble, exhibit low affinity for their target complementary RNA sequences, and target RNase-H poorly.…”

Frequent polymorphism in BCR exon b2 identified in BCR-ABL positive and negative individuals using fluorescent hybridization probes

“…Therefore, probes spanning this region should be avoided. 12,27 In the past decade, antisense oligonucleotides 15,28,29 and…”

“…However, since the alteration is located close to the fusion region it may have a significant influence on the annealing of PCR primers, probes for real time PCR 5,[9][10][11][12][13] and therapeutic antisense oligonucleotides. 14,15 Currently, the frequency of this polymorphism and therefore the potential impact is unknown.…”

BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia

“…Some studies suggest that the inhibition was sequence dependent but not sequence specific (Mahon et al, 1995;O'Brien et al, 1994). Other investigators reported that inhibition of CML cell proliferation by AS-ODNs is sequence specific but nonantisense mediated (Clark, 2000;Vaerman et al, 1995Vaerman et al, , 1997.…”

“…Although BCR/ABL may in theory be the most attractive target for antisense therapy, the long half life of P210 BCR/ABL (more than 24 h) poses a significant obstacle (Clark, 2000;Spiller et al, 1998a,b). Prolonged ex vivo culture would therefore be needed to induce cell death in most leukemic cells, which may interfere with engraftment ability of hematopoietic progenitors.…”