The antisense
drug G3139 (
oblimersen sodium, Genta, Inc.) is a phosphorothioate
oligodeoxynucleotide (ODN) containing unmethylated CpG units, which is targeted to suppress Bcl-2. To date, its effectiveness in
cancer clinical trials has been minimal. Some suggestions are provided for that disappointment and recent citations are provided that support the idea that
G3139 may be effective at clearing
viral infections, specifically HIV. At the time
G3139 was conceived as an anti-
cancer drug candidate, it was viewed optimistically because Bcl-2 was widely believed to be the most important
protein blocking p53-dependent apoptosis caused by internal stress. Since that time, we have learnt that Bcl-2 is not the only
protein that inhibits apoptosis and that p53 itself is frequently malfunctioning in
tumors. Thus, the anti-
cancer utility of suppressing Bcl-2 in
cancer cells is limited. Moreover, Bcl-2 has a role in halting the cell cycle (though p27), which may slow down
tumor growth; and Bcl-2 even has pro-apoptotic roles in the execution of apoptosis initiated by external death signals (via Fas/CD95 and
caspase 3). Overall, in the clinical setting,
G3139 usually has statistically significant but medically unimportant benefit. These results have greatly diminished the enthusiasm for the
drug especially when the side effects are considered. Specifically, the unmethylated
CpG ODN (and/or the phosphorothioate group) activates the immune system, but this potentially important anti-
cancer effect is lost when the immune cells undergo premature apoptosis apparently because their Bcl-2 levels have been lowered by the antisense effect of
G3139. While this effect on immune cells is usually undesirable, it is exactly what would be useful for activating immune cells, initiating provirus transcription in retrovirus-infected cells, and facilitating selective apoptosis of these infected cells. In general,
G3139 might have benefit in clearing
chronic infections by intracellular parasites including viruses (HIV, SIV, HTLV, HBV, coronavirus, etc.). Indeed,
G3139 has been shown to cause apoptosis in EBV-infected cells leading to clearance of the virus.