Down-regulation of human adenovirus E1a by E3 gene products: evidence for translational control of E1a by E3 14{middle dot}5K and/or E3 10{middle dot}4K products

Zhang, Xiaoliu; Bellett, A. J. D.; Hla, Ron Tha; Voss, Tracey; Müllbacher, Arno; Braithwaite, Antony W.

doi:10.1099/0022-1317-75-8-1943

Cited by 12 publications

(6 citation statements)

References 40 publications

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“…Side by side comparison of the two CRAds showed that the presence of the entire E3 region was detrimental to CRAd activity, leading us to pursue the experiments with the CRAd lacking the E3 region. The detrimental effect of the entire E3 region was consistent with previous data showing that the E3 products 14.5K and 10.4K down-regulated E1A at the translational level (41). However, more recent evidence indicates that restoration of the E3 adenoviral death protein or even the entire E3 coding region might enhance CRAd activity (42 -44), strongly suggesting that AV22EL lytic activity could be greatly improved by adding the adenoviral death protein coding region without losing tumor specificity.…”

Section: Discussionsupporting

confidence: 80%

A Novel A33 Promoter–Based Conditionally Replicative Adenovirus Suppresses Tumor Growth and Eradicates Hepatic Metastases in Human Colon Cancer Models

Cafferata

Macció

López

et al. 2009

Clinical Cancer Research

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Purpose: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). Experimental Design: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. Results: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. Conclusions: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC.Colorectal cancer (CRC) is the second most common cause of cancer mortality in Western countries and claimed >50,000 lives a year only in the United States. 4 Close to 70% of patients that are affected by colorectal carcinoma undergo surgical resection and 30% to 40% of them develop a recurrent disease (1). The liver is the most common site of metastatic CRC and complete resection of hepatic metastases is the only curative option; however, surgery can be done only in 20% of patients at the time of diagnosis and 5-year survival rates average 25% to 40% despite adjuvant chemotherapy (2). Among patients with metastatic colorectal carcinoma receiving as first-line chemotherapy 5-fluorouracil (5-FU) and new medications, such as irinotecan, Xeloda, oxaliplatin, Erbitux, and Avastin, the median time to progression is 8 to 9 months and their mean survival is 15 to 20.5 months (3 -6). It seems therefore that current CRC treatments are rather ineffective on advanced disease, showing the need for more effective and specific therapeutics to significantly increase patients' survival.Conditionally replicative oncolytic adenoviruses (CRAd) have shown promising applications in cancer gene therapy (7,8). One strategy to achieve specific elimination of the tumor mass, avoiding negative undesired effects in contiguous normal tissue, is the use of tumor-selective transcriptional regulation to control the essential early E1 genes, whic...

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Section: Discussionsupporting

confidence: 80%

A Novel A33 Promoter–Based Conditionally Replicative Adenovirus Suppresses Tumor Growth and Eradicates Hepatic Metastases in Human Colon Cancer Models

Cafferata

Macció

López

et al. 2009

Clinical Cancer Research

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“…These results suggest that an E3B-deleted virus may have a growth advantage over the wild-type virus. The presence of the E3B gene complex RID has been reported to negatively affect E1A protein expression 36 and may play a role in the observed CPE phenotype of the E3B-deleted viruses. Further experiments are planned to address this observation more rigorously.…”

Section: Figure 6 Murine Tnf Produced By Onyx-321 Kills Susceptible Cmentioning

confidence: 99%

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region

Hawkins

Hermiston²

2001

Gene Ther

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“…Even for the more extensively characterized HAVs, knowledge of virulence is still rudimentary. Studies to date have largely centered around the involvement of the E3 region of the HAV genome in pathogenicity (11,13,41,44), although this focus does not exclude the possible involvement of other regions of the genome (for example, the E1 region has also been implicated) (13,45).…”

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confidence: 99%

“…In addition, the 14.7K, 14.5K, and 10.4K proteins are all involved in avoidance of cell lysis by tumor necrosis factor (14,15,20). The E3 14.5K and/or 10.4K products also interact with the E1a region (45) to reduce E1a protein levels, including the immunodominant cytotoxic T-cell antigen. Down regulation of this antigen protected infected cells from cytolysis (27).…”

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confidence: 99%

A single gene encoding the fiber is responsible for variations in virulence in the fowl adenoviruses

Pallister

Wright

Sheppard

1996

J Virol

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Intertypic recombinant fowl adenoviruses (FAVs) were generated to determine regions of the viral genome involved in virulence. Recombinants were produced with two serotype 8 FAVs, mildly virulent CFA 3 and hypervirulent CFA 40. Restriction endonuclease fragments from the genomes of the two FAVs were used to transfect primary chicken kidney cells. Virulence testing of these recombinants located the region responsible for differences in virulence to an 8.4-kb fragment of the genome located between kb 26.6 and 35.0. According to data available for a serotype 10 FAV that had been partially characterized in the laboratory, this segment of the genome contained three genes of known identity (100K, 33K, and pVIII) and a region between kb 31 and 35 with unknown coding potential (although this information subsequently became available for a serotype 1 FAV, CELO). Therefore, the region between kb 30.5 and 34.5 was sequenced. The results revealed that the unknown region encoded a fiber gene on the right strand and several small open reading frames of unknown identity on the left strand. Further recombinant viruses containing defined exchanges within the 4-kb fragment were constructed, and virulence testing of these viruses indicated that the fiber was responsible for differences in virulence for CFA 40 and CFA 3.

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Down-regulation of human adenovirus E1a by E3 gene products: evidence for translational control of E1a by E3 14{middle dot}5K and/or E3 10{middle dot}4K products

Cited by 12 publications

References 40 publications

A Novel A33 Promoter–Based Conditionally Replicative Adenovirus Suppresses Tumor Growth and Eradicates Hepatic Metastases in Human Colon Cancer Models

A Novel A33 Promoter–Based Conditionally Replicative Adenovirus Suppresses Tumor Growth and Eradicates Hepatic Metastases in Human Colon Cancer Models

Gene delivery from the E3 region of replicating human adenovirus: evaluation of the E3B region

A single gene encoding the fiber is responsible for variations in virulence in the fowl adenoviruses

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