Oblimersen an antiBcl2 antisense ODN in clinical evaluation

A validated molecular target by itself is of no direct therapeutic use, without an effective and safe drug interfering with that target. In addition, the lack of specificity of a drug towards a single target can be misleading regarding the functional role of a protein within a cell.

There were always some manifested concerns about the Bcl-2-unrelated effects elicited by G3139 ODN. In vitro, G3139 ODN cytotoxicity in PC3 prostate cancer cells is independent of Bcl-2 downregulation and correlates with the expression of stress inducible genes [283, 284]. In melanoma cells, it triggers cytochrome c release and therefore apoptosis, presumably by interacting directly with a mitochondrial channel (VDAC) [285]. Moreover, the potent antitumoral effect in murine models of human cancer, including SCLC, is in part due to stimulation of innate immune responses [286].

The success of the initial in vivo mice experiments with G3139 ODN (Oblimersen sodium) contributed decisively to build the confidence around BCL2 as an important target for therapeutic intervention. After the favorable results in phase III trials against melanoma and chronic lymphocytic leukemia [48, 287], a further phase III trial (AGENDA trial) was recently initiated in melanoma patients. However, the phase II clinical trial of G3139 ODN, in combination with carboplatin and etoposide in SCLC patients with extensive disease, did not result in an improved therapeutic outcome [56]. Nonetheless, it is important to point out that such result might be due to inefficient delivery to tumor cells, and therefore these results do not rule out per se a possible therapeutic advantage under improved delivery conditions.

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