Antisense oligonucleotide, apoptosis

Oblimersen sodium is a DNA antisense oligonucleotide designed to specifically bind to human bcl-2 mRNA, resulting in catalytic degradation of bcl-2. This results in decreased translation of the protein Bcl-2, which is a cellular antiapoptotic protein. Thus, oblimersen enhances sensitivity to chemotherapy by shifting the intracellular balance to a state in which the cells are more likely to be killed by apoptosis. Currently, it is used in combination chemotherapy for treating advanced melanoma. 

Antisense oligonucleotides directed against PKC II led to loss of proliferative capacity in K562 cells (Murray et al., 1993). Dowmnodulation of PKC by antisense had no effect on the proliferation and saturation density in K562 cells (Murray et al., 1997). However, Spitaler et al. (1999) found that down-modulation of PKC with antisense oligonucleotides in HeLa cells led to the induction of apoptosis. 

The Bcl-2 family has been extensively investigated and has become the target of many approaches to modulate its expression and function. Bcl-2 antisense oligonucleotides are able to induce apoptosis in leukemia cell line and primary cells, and enhance chemotherapy-induced apoptosis (K4). This approach has already been implemented successfully in a phase I study in treating lymphoma patients (W7). 

K4. Konopleva, M., Tari, A., Lopez-Berestein, A., and Andreeff, M., Inhibition of Bcl-2 with liposomal-derived antisense oligonucleotides (AS-ODN) induces apoptosis and increases the sensitivity of primary acute myeloid leukemia (AML) cells and cell lines to cytosine arabi-noside and doxorubicin. Blood 90 (suppl. 1), 10494a (1997). 

Zhang XX, Cui CC, Xu XG, Hu XS, Fang WH, Kuang BJ. In vivo distribution of c-myc antisense oligonucleotides local delivered by gelatin-coated platinum-iridium stent in rabbits and its effect on apoptosis. Chin MedJ (Engl) 2004 I 17(2) 258-263. 

Changes in IAP expression modulate apoptotic response to cellular stress. For example, an antisense oligonucleotide developed by Aegera Therapeutics, Inc. (Montreal, Quebec, Canada), AEG35156, reduces expression of XIAP. Treatment with AEG3516 increases apoptosis in studies with myeloid leukemia cells, and the antisense approach currently is in phase Eli clinical trials for refractory AML (acute myeloid leukemia) in combination with chemotherapy (29). The strategy of up-regulating IAP action to inhibit apoptosis has been validated... 

Hu Y, Cherton-Horvat G, Dragowska V et al (2003) Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin Cancer Res 9(7) 2826-2836... 

It has not yet been established whether c-Myc is involved in developmental cell death in vivo. Circumstantial evidence for c-Myc involvement comes from the following observations (1) c-myc mRNA is increased following activation of the TCR in immature thymocytes (Riegel et al, 1990), (2) c-myc antisense oligonucleotides inhibit TCR-induced apoptosis in T cell hybridomas (Green et al, 1992 Shi et al, 1992) and (3) Myc-Max heterodimers are necessary for AICD in these cells (Bissonnette et al.,... 

Abenant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of hepatitis. The possibility was studied tliat inhibition of Fas expression in mice would reduce the severity of fulminant hepatitis. To do this, a chemically modified 2 -C-(2-niethoxy)ethyl antisense oligonucleotide (ISIS 22023) inhibitor of mouse Fas expression was developed. In tissue culture, this oligonucleotide induced a reduction in Fas iiiRNA expression that was both concentration- and sequence-specific. In BALB/c... 

A number of experimental studies have shown that caspase inhibition reduces ischemic injury [51]. Caspase-3 inhibitors [52], gene deletions of Bid or caspase-3 [53], and the use of peptide inhibitors, viral vector-mediated gene transfer, and antisense oligonucleotides that suppress the expression and activity of apoptosis genes have all been found to be neuroprotective [51]. However, caspase inhibitors do not reduce infarct size in all brain ischemia models, perhaps related to the greater severity of ischemia, limited potency or inability of the agent to cross the blood-brain barrier, relatively minor impact of apoptosis on stroke outcome, and upregulation of caspase-independent or redundant cell-death pathways. Ultimately, it may be necessary to combine caspase inhibitors and other inhibitors of apoptosis with therapies directed toward other pathways, for successful neuroprotection. 

Ackermann EJ, Taylor JK, Narayana R et al. The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem 1999 274 11245-11252. 

Zangemeister-Wittke U, Leech SH, Olie RA, Simoes-Wust AP, Gautschi O, Leudke GH, Natt F, Haner R, Martin P, Hall J et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. CUn Cancer Res 2000 6 2547-2555. 

Dai LC, Wang X, Yao X, Lu YL, Ping JL, He JF. Antisense oligonucleotides targeting midkine induced apoptosis and increased chemosensitivity in hepatocellular carcinoma cells. Acta Pharmacol Sin. 2006 27 1630-6. 

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