Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells

Lowe, S; Rubinchik, Semyon; Honda, Tsuyoshi; McDonnell, Timothy J.; Dong, Jian-Yun; Norris, James S.

doi:10.1038/sj.gt.3301531

Cited by 73 publications

(47 citation statements)

References 35 publications

(45 reference statements)

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“…[1][2][3][4][5][6][7][8][9][41][42][43][44][45][46] In Figure 6 Influence of orientation and distance of the expression cassettes for p53-dependent transcriptional repression in a double transgene adenoviral shuttle plasmid. (d) The CMV gal-5 luciferase reporter cassette and the transcriptional repressor cassettes (GAL4-KRAB-A and GAL4-SIN3B-SF) under control of prMin-RGC were cloned into the adenoviral shuttle plasmid in different orientations as indicated.…”

Section: Discussionmentioning

confidence: 99%

“…Besides retargeting adenoviral vectors by genetical modifications of the fiber protein, many attempts have been made to target therapy to cancer cells by using tumor selective promoters such as AFP-, CEA-, PSA-or hTERT-promoter. [1][2][3][4][5][6][7][8][9][10] Using this approach, tumor specificity has been achieved at the cost of 50-300-fold loss in transcriptional activity compared to the strong but nonselective CMV-promoter. Other important limitations of gene therapy targeting by tumor-specific promoters are the heterogenous strength of these promoters in different tumor cells within a tumor nodule and the wide variety of promoter activities in different tumors.…”

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confidence: 99%

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Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways

et al. 2003

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Adenoviral gene expression that is repressed by p53 in nontransformed cells could provide a tumor-specific gene therapy approach for a large subset of tumors. Adenoviral infection in vivo induces stabilization of p53, which can be utilized for a strategy that includes p53-dependent expression of a transcriptional repressor and a target promoter ,which is highly susceptible for transcriptional repression. Therefore, we constructed different versions of CMV-promoters (CMV gal ) with binding sites for GAL4-DBD and investigated 11 GAL4-DBD fusion proteins to elucidate the most effective repressor domain to silence CMV gal activity.The transcriptional repressor GAL4-KRAB-A under control of a p53-dependent promoter facilitates strong CMV gal -mediated gene expression specifically in p53 mutant cells by a double-recombinant adenoviral vector (Ad-RGCdR). GAL4-KRAB-A mediates strong transcriptional repression of Ad-RGCdR in p53 wild-type cells, which could be further enhanced by preactivation of p53-signalling following low-dose chemotherapy prior to adenoviral infection. By utilizing p53 signalling involved in chemotherapy and adenoviral infection, more than 99% of Ad-RGCdR gene expression could be repressed in p53 wild-type cells. Controlled gene expression from CMV gal promoters by transcriptional repression utilizing functional p53 signalling thus provides a very effective tool for tumor-specific adenoviral gene therapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways

et al. 2003

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“…The vectors so constructed are referred as FUTK or FULW, respectively. A modified probasin promoter (ARR 2 PB) [35][36][37][38] was cloned at Pac1 and BamH1 site into vector FUGW earlier cut with Pac1 and BamH1 to remove the ubiquitin promoter. The DNA fragment coding for luciferase was cloned into the vector under the control of the ARR 2 PB promoter to create the lentiviral vector FALW.…”

Section: Construction and Preparation Of Lentiviral Vectorsmentioning

confidence: 99%

“…K-x Zhang et al under the control of a modified probasin promoter (ARR 2 PB), [35][36][37][38] whose expression is prostate specific. 38 This viral vector, referred to as FALW/SB, was incubated with trastuzumab and then injected i.v.…”

Section: Her-2 Targeting Of Prostate Cancermentioning

confidence: 99%

“…As the probasin-derived ARR 2 PB promoter has been shown to be capable of directing tightly controlled prostate-specific gene expression, [35][36][37][38] we placed it in front of the firefly luciferase gene in an attempt to increase tumor-specific expression. Indeed, the luminescent signal from cells infected with the trastuzumab-bound lentivirus containing the ARR 2 PB promoter was entirely restricted to the tumors (Figure 7b).…”

Section: Her-2 Targeting Of Prostate Cancermentioning

confidence: 99%

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Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Moussavi

et al. 2009

Cancer Gene Ther

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In this study, we took advantage of the overexpression of human epidermal growth factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with modified envelope proteins that bind antibodies to specific cell-surface antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses were able to selectively infect androgen-sensitive LNCaP and castrationresistant C4-2 human prostate cancer cell lines, both of which express high levels of HER-2. To test for a therapeutic effect, we engineered our antibody-binding lentiviruses to express thymidine kinase, which can convert the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2 cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2 xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound lentivirus expressed luciferase, although the latter route was less tumor specific. When a prostate-specific promoter for governing luciferase expression was combined with trastuzumab-mediated delivery, there was a further enrichment in targeting viral gene expression in prostate tumors. In conclusion, we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody.

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Why do DES not alter long‐term outcomes? Why would they, after all, it's a chronic disease

Dean

2007

Cathet Cardio Intervent

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In this issue of the journal, Garcia-Garcia et al. report on 3-year outcomes in a group of patients undergoing DES stenting for chronic total occlusion compared to a historical BMS control group. As previously reported by this group and others, short-term outcomes seem to be superior with DES stenting, at least out to 1 year. Why the apparent equivalent outcomes at 3 years?Coronary disease is a chronic disease that, given similar patient populations, should progress at similar rates yielding similar long-term outcomes irrespective of the stent type used. There is no doubt, in CTO as well as non-CTO lesions, that stents treat only the relatively small section of the diseased vessel in which they are implanted. BMS impacts restenosis by overwhelming the impact of late loss by maximizing the initial result and eliminating negative remodeling. They have no impact on the chronic disease. Drug eluting stents have the additional impact of truncating the healing process resulting in mitigation of late loss. Drug eluting stents also have no impact on the longterm disease process within the implanted vessel or obviously anywhere else for that matter. Atherosclerosis affects all the coronaries to a variable degree, and it is also a systemic disease as well. A device that is generally less than 1-in. long and elutes a drug for a relatively short period of time could not possibly impact long-term outcome. What does? Without a doubt it is medical therapy of the underlying disease. This is a systemic treatment for a systemic disease.Unfortunately, Garcia-Garcia et al. do not report the medical therapy given to these patients outside of antiplatelet drugs. The evidence base supporting medical therapy of coronary disease is large and convincing. In large part it is very likely to explain the drop in cardiovascular death in the United States over the last several years. To some degree medical therapy is also likely to explain part of the drop in the number of coronary bypass operations performed in this country with a hint of an impact on percutaneous coronary intervention rates, well before the recent controversies and the wide use of DES.It is time to start collecting and reporting the medical therapy of patients undergoing coronary intervention. Otherwise, how will we ever really know what is responsible for long-term outcomes? Is it the stent or the underlying disease and/or its medical management? As we go forward with registries and randomized trials designed to look at the long-term impact of DES, we must know this information. Hear my plea!

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Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells

Abstract: In prostate carcinoma, overexpression of the anti-apoptotic gene

Cited by 73 publications

References 35 publications

Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways

Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal transduction pathways

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Why do DES not alter long‐term outcomes? Why would they, after all, it's a chronic disease

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