Oblimersen

Description

As the representative antisense oligonucleotide, oblimersen is an 18-base phosphor- othioate antisense oligodeoxynucleotide that was developed to treat CLL, B-cell lymphoma, lung, and breast cancers. Oblimersen binds with the first six codons of Bcl-2 mRNA open reading frame and mediates RNA cleavage by RNase H to downregulate Bcl-2. The antitumor effect of oblimersen is associated with both apoptotic and nonapoptotic pathways.
In the apoptotic pathway, Bcl-2 downregulation by oblimersen could increase Bax and poly (ADP-ribose) Polymerase (PARP) to release cytochrome cand Smac/DIABLO to pro- mote apoptosis. For the nonapoptotic pathway, Bcl-2 downregulation by oblimersen may have promoted the release of Beclin-1 to induce autophagic cell death. In addition, oblimersen has been shown to enhance tumor immunity by promoting polyclonal antibodies production and activating dendritic cell maturation. In monotherapy, oblimersen failed in phase-III clinical trials of treating lymphoid malignancies, which could be due to limited uptake, intracellular compartmentalization, or degradation by nuclear enzymes. On the other hand, oblimersen has been found to increase the overall survival when combined with other chemotherapeutic drugs, such as dacarbazine, fludarabine, and cyclophosphamide, by increasing the sensitivity of those drugs.