As the representative antisense oligonucleotide, Oblimersen (G3139, Genasense) 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.
Genta is developing a phosphorothioate antisense drug called oblimersen sodium that is complementary to the first six codons of the open reading frame of the human bcl-2 mRNA sequence. Oblimersen turns off production of the apoptosis inhibitor Bcl2 in tumor cells. This appears to increase a tumor cell's sensitivity to a variety of other anticancer therapies and, ultimately, may lead to cell death.
