BCL-2 antisense therapy in patients with non-Hodgkin lymphoma

Webb, Andrew R.; Cunningham, David; Cotter, Finbarr E.; Clarke, Paul A.; Stefano, Francesca Di; Ross, Paul; Corbo, M; Dziewanowska, Zofia E.

doi:10.1016/s0140-6736(96)11103-x

Cited by 450 publications

(179 citation statements)

References 12 publications

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“…In addition, because many tumors have increased Bcl-x L expression (Olopade et al, 1997;Kirsh et al, 1998;Krajewski et al, 1996Krajewski et al, , 1997Kondo et al, 1996), this approach may provide a powerful approach to treating cancer. In support of this hypothesis, a recent study examined the e cacy of using Bcl-2 antisense inhibitors to treat non-Hodgkin's lymphoma in the clinic (Webb et al, 1997). The results of this study suggest that the use of inhibitors to cell survival regulators may be a feasible and bene®cial therapeutic approach to the treatment of multiple types of cancers.…”

Section: Discussionmentioning

confidence: 82%

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

et al. 1999

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The epidermis is continually exposed to harmful mutagens that have the potential to cause DNA damage. To protect the skin from accumulating mutated cells, keratinocytes have developed a highly regulated mechanism of eliminating damaged cells through apoptosis. Bclx L is a well-described cell survival protein that when overexpressed in skin can protect keratinocytes from UV radiation-induced apoptosis. To begin to unravel the complex mechanisms that keratinocytes use to survive, we wanted to characterize the role of endogenous Bcl-x L in protecting cells from death. In this study, we describe the development and characterization of an antisense inhibitor to Bcl-x L . We show that this inhibitor reduces Bcl-x L RNA and protein in a concentration-dependent, sequence-speci®c manner. Furthermore, treatment of keratinocytes and epithelial cells with this inhibitor sensitizes these cells to UV-B radiation and cisplatinum treatment-induced apoptosis. Thus, these results o er direct evidence that Bcl-x L is critical in the protection of skin and epithelial cells from apoptosis and provide a basis for the role of Bcl-x L in keratinocyte and epithelial cell survival.

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Section: Discussionmentioning

confidence: 82%

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

et al. 1999

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“…AS and control ODNs were added to the cells in the form of complexes with cationic lipopolyamine according to the manufacturer's protocol, as described previously. 25 Briefly, the medium was removed, and serum-free RPMI was added to the cells. The ODN-lipopolyamine complex was prepared and added dropwise to the cells.…”

Section: Treatment With As Bcl-2 Oligonucleotidementioning

confidence: 99%

Modulation of tamoxifen sensitivity by antisense Bcl‐2 and trastuzumab in breast carcinoma cells

Kim

Tanabe

Emi

et al. 2005

Cancer

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BACKGROUNDBecause the overexpression of HER‐2 and Bcl‐2 is associated with resistance to tamoxifen (TAM), the authors examined the effect of antisense (AS) Bcl‐2 on sensitivity to TAM compared with the effect of trastuzumab on sensitivity to TAM in breast carcinoma cell lines.METHODSDrug sensitivity was assessed in vitro using a [3‐4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay with the breast carcinoma cell lines ZR‐75‐1, MDA‐MB‐453, and BT‐474. AS Bcl‐2 18‐mer phosphorothioate oligonucleotide was applied. Apoptotic cell death was assessed with the terminal deoxynucleotidyl transferase‐mediated biotinylated UTP nick‐end labeling method, and gene expression was evaluated with Western blot analysis.RESULTSThe expression of Bcl‐2 was identified in ZR‐75‐1 and BT‐474 cells and, to a lesser extent, in MDA‐MB‐453 cells. Overexpression of HER‐2 was identified in BT‐474 cells, and moderate expression was identified in MDA‐MB‐453 and ZR‐75‐1 cells. Combination treatment with trastuzumab or AS Bcl‐2 enhanced TAM sensitivity in ZR‐75‐1 cells, which showed 50% inhibitory concentration (IC50) values of 0.9 μM (7.2‐fold increase) and 0.5 μM (13.0‐fold), respectively. Combination treatment with trastuzumab or AS Bcl‐2 slightly enhanced TAM sensitivity of BT‐474 cells, with IC50 values of 3.0 μM (1.3‐fold) and 1.5 μM (2.6‐fold), respectively. The sensitivity of MDA‐MB‐453 cells to TAM was not enhanced by combination with trastuzumab or AS Bcl‐2. Modulation of TAM sensitivity by AS Bcl‐2 was superior to modulation by trastuzumab in HER‐2‐expressing and Bcl‐2‐expressing breast carcinoma cells. Enhanced sensitivity in combination with AS Bcl‐2 was associated with down‐regulation of Bcl‐2 and pAkt, which was correlated with the induction of Bax and caspase‐3, leading to apoptosis.CONCLUSIONSAS Bcl‐2 appeared to be superior to trastuzumab with respect to regulating the signal‐transduction pathways involved in breast carcinoma cells. Cancer 2005. © 2005 American Cancer Society.

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“…14,16 -19 Bcl-2 is an attractive therapeutic target for both hematologic malignancies and solid tumors, including melanoma. [17][18][19][20][21][22][23] The antiapoptotic Bcl-2 family member Bcl-x L , which has been studied in lesser detail, may prove to be an even more attractive therapeutic target.…”

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confidence: 99%

Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Heere-Ress

Thallinger

Lucas

et al. 2002

Intl Journal of Cancer

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Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x L is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x L protein as a potential therapeutic target in melanoma, the influence of Bcl-x L expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x L in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p < 0.05). In a parallel approach, reduction of Bcl-x L protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x L is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x L expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.

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BCL-2 antisense therapy in patients with non-Hodgkin lymphoma

Cited by 450 publications

References 12 publications

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Modulation of tamoxifen sensitivity by antisense Bcl‐2 and trastuzumab in breast carcinoma cells

Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

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BCL-2 antisense therapy in patients with non-Hodgkin lymphoma

Cited by 450 publications

References 12 publications

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli

Modulation of tamoxifen sensitivity by antisense Bcl‐2 and trastuzumab in breast carcinoma cells

Bcl‐XL is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

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Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy