COMPARISON OF DIFFERENT ANTISENSE OLIGONUCLEOTIDES AGAINST THE BCR ABL JUNCTION IN CHRONIC MYELOGENOUS LEUKEMIA - CELLULAR PHARMACOLOGY ANDIN-VITRO EFFICACY/

The activity of the BCR/ABL hybrid gene is associated with a growth ad vantage of the chronic myelogenous leukemia (CML) stem cell. Suppressi on of BCR/ABL hybrid gene expression can be a valuable tool for leukem ic cell purging. Antisense oligonucleotides (ODNs) have the capacity t o specifically downregulate gene expression. Data reported on the effe ct they have on BCR/ABL hybrid gene expression are controversial. We p resent data illustrating that prolongation of ODN half-life by means o f chemical or sequence modification has only limited specific growth s uppressive effect on BCR/ABL-positive clonogenic cells in vitro. Compa red to unmodified phosphodiester ODNs (PO-ODNs) spanning the BCR/ABL j unctions, modified ODNs with either a 3'-GC-clamp (GC-ODNs) or ODNs wi th one 3'-inverted nucleotide (3'-3' ODNs) to prevent 3'-exonuclease d egradation, showed significantly prolonged extra- and intracellular ha lf lives and different subcellular distributions in CML cell lines. In clonogenic assays from patients with CML, the modified ODNs were to s ome extent able to reduce colonies expressing BCR/ABL (GC-ODNs >3'-3'- ODNs >PO-ODNs). This difference did not become significant statistical ly. We demonstrate a substantially diminished hybridization efficacy o f the modified antisense ODNs used, which may serve as a possible expl anation for the failure to augment the leukemic cell purging efficacy.