Why G3139 works poorly in cancer trials but might work well against HIV.
Why G3139 works poorly in cancer trials but might work well against HIV.
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DOI：
10.1016/j.mehy.2007.01.044
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发表时间：
2007
影响因子：
4.7
通讯作者：
Parris GE
中科院分区：
文献类型：
--
作者：
Parris GE
反义药物G3139 （oblimersen sodium, Genta, Inc.）是一种含有未甲基化CpG单位的磷酸硫代寡脱氧核苷酸（ODN），其靶向抑制Bcl-2。迄今为止，它在癌症临床试验中的有效性微乎其微。对于这种失望，作者提出了一些建议，并提供了最近的引用，支持G3139可能有效清除病毒感染，特别是HIV的观点。当G3139被认为是一种抗癌候选药物时，人们对其持乐观态度，因为人们普遍认为Bcl-2是阻断内应激引起的p53依赖性细胞凋亡的最重要蛋白。从那时起，我们了解到Bcl-2并不是唯一抑制细胞凋亡的蛋白质，p53本身在肿瘤中经常出现故障。因此，抑制Bcl-2在癌细胞中的抗癌作用是有限的。此外，Bcl-2具有停止细胞周期的作用（尽管p27），这可能会减缓肿瘤的生长；Bcl-2甚至在外部死亡信号（通过Fas/CD95和caspase 3）启动的细胞凋亡执行中具有促凋亡作用。总体而言，在临床环境中，G3139通常具有统计学上显著但医学上不重要的益处。这些结果大大降低了人们对这种药物的热情，尤其是考虑到副作用时。具体来说，未甲基化的CpG ODN（和/或硫代酸基团）激活免疫系统，但当免疫细胞发生过早凋亡时，这种潜在的重要抗癌作用就会丧失，这显然是因为它们的Bcl-2水平被G3139的反义作用降低了。虽然这种对免疫细胞的影响通常是不可取的，但它正是激活免疫细胞、启动逆转录病毒感染细胞中的前病毒转录和促进这些感染细胞选择性凋亡的有用物质。总的来说，G3139可能对清除细胞内寄生虫（包括病毒（HIV、SIV、HTLV、HBV、冠状病毒等））引起的慢性感染有好处。事实上，G3139已被证明在ebv感染的细胞中引起细胞凋亡，导致病毒被清除。
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.
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DOI：
10.2174/1568011033482396
发表时间：
2003-07-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Bettaieb, Ali;Dubrez-Daloz, Laurence;Solary, Eric
通讯作者：
Solary, Eric
影响因子：
8
作者：
Cheng, NL;Janumyan, YM;Knudson, CM
通讯作者：
Knudson, CM
影响因子：
4.7
作者：
Parris, GE
通讯作者：
Parris, GE
影响因子：
5.5
作者：
Pauls, Eduardo;Senserrich, Jordi;Este, Jose A.
通讯作者：
Este, Jose A.
影响因子：
8
作者：
Del Bello, B;Valentini, MA;Maellaro, E
通讯作者：
Maellaro, E