Tumor cell-specific transgene expression prevents liver toxicity of the adeno-HSVtk/GCV approach

Brand, Karsten; Löser, Peter; Arnold, W; Bartels, Th; Strauß, Michael

doi:10.1038/sj.gt.3300728

Cited by 67 publications

(40 citation statements)

References 17 publications

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“…The CEA promoter can be applied to diverse cancers in which this gene is overexpressed, such as gastric carcinoma [23] and colorectal cancer [24]. Adenoviral vectors carrying CEA promoterdriven therapeutic genes were able to mediate targeted expression, tumor regression and prolonged survival in CEA + tumor-bearing mice [25], with minimal liver toxicity [26]. Because AFP and CEA are used as serum diagnostic markers in several carcinomas [27,28], employing these promoters as targets would be supported in expression-positive carcinomas.…”

Section: Transcriptional Targetingmentioning

confidence: 99%

Transcriptionally targeted gene therapy to detect and treat cancer

Wu¹,

Johnson²,

Sato³

2003

Trends in Molecular Medicine

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The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a 'one-two punch' to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.Multiple genetic alterations that confer growth advantages to tumor cells are accumulated during the transformation from normal to neoplastic growth [1]. The loss of growth suppressive genes or gain of oncogenes constitutes a common mechanism of oncogenesis. Based on this information, a rational therapeutic approach is to re-introduce the defective growth control genes into tumor cells. In addition, approaches of inducing apoptotic responses and enhancing anti-tumor immune responses have also been employed [2]. Due to the availability of multiple flexible therapeutic strategies, gene therapy is being actively investigated in clinical settings.Among the ~ 40 ongoing gene therapy clinical trials for cancer (searched via www.clinicaltrials.gov/), 18 of the trial protocols involve an immune activating scheme, ten studies employ a genetic correction strategy and five use a cytotoxic gene. With regard to genetic correction strategies, p53 is a major target. The recombinant adenovirus is the dominant viral gene delivery vector, and it is employed in 18 protocols. However, none of 40 protocols use a cancer-specific gene expression strategy. An oncolytic adenovirus CN706 containing prostate-specific antigen (PSA) promoter driven viral replication [3] is being evaluated in phase II clinical trial for prostate cancer [4].Because the goal of cancer gene therapy is to eradicate cancer cells, many therapeutic genes could be detrimental if unintentionally expressed in normal cells. Selectively targeting the cancer cells is useful to achieve safety and efficacy, especially when the gene therapy vector is directly delivered into patients. Based on features that distinguish cancerous from normal cells, three targeting strategies could be employed. Transcriptional targeting takes advantage of the fact that some cancer cells express a subset of exclusive genes, and uses these cancerspecific promoters to express the desired transgenes [5]. Transductional targeting refers to surface modification on the gene delivery vehicle to enhance interactions with the cancer cell membrane antigen, thereby improving gene transfer into the cancerous cell. A third promising approach is to exploit cancer-a...

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Section: Transcriptional Targetingmentioning

confidence: 99%

Transcriptionally targeted gene therapy to detect and treat cancer

Wu¹,

Johnson²,

Sato³

2003

Trends in Molecular Medicine

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“…37 It has been shown that Ad virus infection of cells can cause cell cycle dysregulation, which is characterized by a G2 -like cell cycle arrest and deregulated expression of cyclins A, B1, D, and cdk p34cdc2 protein levels. 59,72 However, the cell cycle disturbances observed in our experiments were clearly due to the overexpression of p16 and not the adenoviral infection itself because irrespective of the genomic status of p16, p53, p21, or bax of tumor cells, infection with various control vectors did not induce significant cell cycle disturbances and apoptosis.…”

Section: Discussionmentioning

confidence: 62%

Adenovirus-mediated gene transfer of P16INK4/CDKN2 into bax-negative colon cancer cells induces apoptosis and tumor regression in vivo

et al. 2002

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The tumor -suppressor gene p16INK4 / CDKN2 ( p16 ) is a cyclin -dependent kinase ( cdk ) inhibitor and important cell cycle regulator. Here, we show that adenovirus -mediated gene transfer of p16 ( AdCMV.p16 ) into colon cancer cells induces uncoupling of S phase and mitosis and subsequently apoptosis. Flow cytometric analysis revealed that cells infected with AdCMV.p16 showed an initial G2 -like arrest followed by S phase without intervening mitosis ( DNA >4N ). Using microscopic analysis, deformed polyploid cells were detectable only in cells infected with AdCMV.p16 but not in control -infected cells. Subsequently, AdCMV.p16 -infected polyploid cells underwent apoptosis, as assessed by AnnexinV staining and DNA fragmentation, suggesting that cell cycle dysregulation is upstream of the onset of apoptosis. Treatment of mice with subcutaneously transplanted tumors of colorectal cancer cells with AdCMV.p16 but not AdCMV.p53 resulted in significantly reduced tumor volume and prolonged survival. Using an orthotopic model of liver metastasis, we observed both reduced local tumor growth and secondary intrahepatic metastasis after AdCMV.p16 treatment. Importantly, induction of apoptosis in vitro and reduction of tumor growth in vivo by p16 was p53 -as well as bax -independent because identical results were obtained using cancer cells, either wild type or mutant for p53 or bax. The studies suggest that an AdCMV.p16 -based treatment may be especially effective in patients with bax -negative colon cancer where overexpression of p53 appears not to be of therapeutic value.

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“…17,20,30 Several tissue-specific promoters have been investigated for their ability to mitigate the liver toxicity associated with TK-mediated 'suicide' gene therapy. 31,32 In the present study, we reasoned that the OBHRE promoter would be suitable for this purpose due to its low basal activity in normal tissue. We compared the in vivo toxicity of the Ad.HRETK and Ad.CMVTK vectors.…”

Section: Hre-mediated Tumour Targetingmentioning

confidence: 92%