Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Fuerer, Christophe; Iggo, Richard

doi:10.1038/sj.gt.3301651

Cited by 63 publications

(71 citation statements)

References 44 publications

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“…Tumor size and mice status were monitored thrice a week. Tumor volume was defined by the equation V (mm 3 ) ¼ p/6 Â W Â L 2 , where W and L are the width and length of the tumor, respectively. The percentage of growth was calculated as ((VÀV 0 )/ V 0 ) Â 100, where V 0 is the tumor volume on day 0.…”

Section: In Vivo Antitumoral Efficacymentioning

confidence: 99%

“…In this regard, tissue-specific promoters have been tested to target cancers arising from specific tissues. 2,3 However, promoters active in a wider range of tumor types increase the patient population potentially benefiting from a new treatment agent. A tight and potent promoter regulated by repression in normal cells and activation in tumor cells might be an ideal option for reaching a high antitumor effect with low toxicity.…”

Section: Introductionmentioning

confidence: 99%

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A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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The E2F-1 promoter has been used to confer tumorselective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-D24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The D24 deletion avoids a loop of E2F-mediated selfactivation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

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Section: In Vivo Antitumoral Efficacymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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“…2 The second strategy targets cancer cells by regulation of the essential viral genes involved in replication, using tumor-or tissue-specific promoters that are preferentially active in tumor cells. A number of exogenous promoters that are preferentially active in tumor cells have been used to control the essential E1a and E1b genes in order to generate oncolytic adenoviruses, including the a-fetoprotein (AFP) promoter for replication in hepatocellular carcinomas, [3][4][5][6] the DF3/ MUC1 or other breast cancer-related promoters for targeting breast carcinomas, 7-10 a Tcf-responsive promoter for colon cancer, 11 and a human tyrosinase promoter for melanoma cells. [12][13][14][15] By using prostate-specific promoters, adenoviral vectors CN706 and CV787 have entered clinical trials for prostate cancer utilizing intraprostatic and intravenous delivery.…”

Section: Introductionmentioning

confidence: 99%

Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

Zheng

et al. 2005

Cancer Gene Ther

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E1B55K-deleted dl1520 could selectively replicate in cancer cells and has been used in clinical trials as an antitumor agent. The mechanism of virus selective replication in cancer cells, including a possible role of p53, is unclear. Studies with established cancer cell lines have demonstrated that some cancer cells are resistant to dl1520 replication, regardless of the p53 status. Hep3B cells supported the E1b-deleted adenoviruses to replicate, whereas Saos2 cells were resistant to viral replication. We applied p53-null Hep3B and Saos2 cells as models to clarify the replication ability of E1B55K-deleted adenoviruses with different expression levels of E1a. We show that lower E1A expression in Saos2 may be the reason for the poor replication in some cancer cells due to the fact that E1a promoter was less activated in Saos2 than in Hep3B. We also demonstrate that the E1B55K protein can increase E1A expression in Saos2 cells for efficient virus replication. In addition, the upstream regions of the E1a promoter have transcriptional activity in Hep3B cells but not in Saos2 cells. The viral E1B55K protein may activate cancer cellular factor(s) that targets the upstream regions of the E1a gene to increase its expression. This is the first study demonstrating that E1B55K protein affects the E1A production levels that is related to cancer selective replication. Our studies have suggested that increase of E1A expression from E1b-deleted adenoviruses may enhance killing cancer cells that otherwise are resistant to viral replication.

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“…The first is deletion or regulated expression of essential viral genes, leading to tumourspecific viral replication. [1][2][3][4][5][6][7][8] In principle, viruses of this type can replicate, lyse the cell, infect nearby cells and spread throughout the tumour mass until all of the tumour cells are killed. The second change is modification of the tropism of the virus.…”

Section: Introductionmentioning

confidence: 99%

5-Fluorocytosine increases the toxicity of Wnt-targeting replicating adenoviruses that express cytosine deaminase as a late gene

Fuerer¹,

Iggo²

2004

Gene Ther

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Clinical studies with oncolytic adenoviruses have shown that existing viruses are safe but lack efficacy. To selectively increase the toxicity of oncolytic adenoviruses targeting colon tumours, we have inserted the yeast cytosine deaminase gene (yCD) after the fibre gene in the major late transcript. yCD was expressed using either an internal ribosome entry site (IRES) or by alternative splicing of a new exon analogous to the Ad41 long fibre exon. The IRES-CD virus gave higher yCD expression on Western blots. Both approaches result in yCD expression restricted to the period after viral DNA replication. Viral burst size was reduced by less than B10-fold by 5-fluorocytosine (5-FC), showing that expression of yCD as a late gene is compatible with virus replication. Cytopathic effect assays in colon cancer cell lines showed that both yCD viruses have B10-fold increased toxicity in the presence of the prodrug 5-FC, which is converted to 5-fluorouracil (5-FU) by yCD. Toxicity was higher following addition of 5-FC immediately after infection. The largest gain in toxicity was seen in HT29 colon cancer cells, which are the least permissive colon cancer cells for the parental virus, indicating that the new 5-FC/yCD viruses may have broader applications for colon cancer therapy than their predecessors.

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Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumour cells with constitutive activation of the wnt signalling pathway

Abstract: Mutation of the adenomatous polyposis coli

Cited by 63 publications

References 44 publications

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

5-Fluorocytosine increases the toxicity of Wnt-targeting replicating adenoviruses that express cytosine deaminase as a late gene

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