Replication-selective viruses for cancer therapy

Biederer, Carola; Ries, Stefan; Brandts, Christian; McCormick, Frank

doi:10.1007/s00109-001-0295-1

Cited by 76 publications

(53 citation statements)

References 95 publications

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“…4,5 Adenovirus dl1520, with deletion of E1B55K, selectively replicates in cancer cells presumably because of p53 deficiency in these cells. 20,21 However, recent studies showed that dl1520 could also replicate in cells expressing WT p53.…”

Section: Discussionmentioning

confidence: 99%

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E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

et al. 2004

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Apoptotic pathways are initiated as a cellular defense mechanism to eliminate adenovirus-infected cells. We have investigated how E1A-induced apoptosis interferes with viral replication in cancer cells. We found that E1B19K alone can efficiently suppress E1A-induced apoptosis in cancer cells. Viruses deleted for both E1B19K and E1B55K resulted in cellular DNA degradation. However, less than 20% of human lung cancer cells infected with a virus deleted for both E1B19K and E1B55 K had evidence of chromatin condensation and multiple-micronuclei formation (apoptotic hallmarks); these cells could not produce infectious viral particles. The majority of cancer cells infected with viruses deleted for the entire E1b gene did not undergo extended apoptosis and produced abundant viral progeny. Thus, only a fraction of cancer cells underwent apoptosis and did not allow E1b-deleted viruses to replicate, while the majority of cancer cells were resistant to E1A-induced apoptosis and could support virus-selective replication. The results of this study imply that, in addition to inhibiting E1A-induced apoptosis, E1B proteins may contribute other important roles in the viral life cycle. Our results also suggest that combining virus-induced apoptosis and selective viral replication into one vector will be a novel approach to destroy cancer cells.

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Section: Discussionmentioning

confidence: 99%

“…High levels of p53 lead to cell growth arrest or apoptosis that is presumed to inhibit viral replication. [3][4][5] Adenoviruses (Ad) have developed measures to overcome host cell apoptosis. The E1b-encoded E1B19K and E1B55K proteins protect the infected cells from these E1A-induced p53 effects.…”

Section: T O Induce the Cells Into S-phase For Effective Viralmentioning

confidence: 99%

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

et al. 2004

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“…Clinical trials have shown that dl1520 as a single anticancer agent cannot efficiently inhibit tumor growth. [50][51][52] One possible explanation for the limited efficacy of dl1520 in the clinical treatments is that some cancer cells within tumors may be resistant to dl1520 replication, just as some established cancer cell lines are resistant to dl1520 replication. Cancer cells that are resistant to viral replication will survive the treatment and continue its growth.…”

Section: Adenoviruses-induced Cell Cycle Changes In Hep3b and Saos2 Cmentioning

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 use of a virotherapy, which employs a conditionally replicative adenovirus, allows the selective replication of virus in target cell types and permits subsequent rounds of viral amplification to greatly increase the antitumor effect. [8][9][10] One of the first examples of an oncolytic adenovirus was Onyx-015, an E1B 55 kDa gene deleted adenovirus, that was designed to replicate exclusively in p53-deleted or mutated tumor cells and has shown encouraging results in clinical trials. 11 Tissue-and tumor-specific promoters have also been incorporated in oncolytic viral vectors to drive selective expression of genes required for viral replication in tumor cells.…”

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confidence: 99%

Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

et al. 2004

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The human telomerase reverse transcriptase (hTERT) promoter is known to selectively drive transgene expression in many human cancer cells expressing hTERT, the catalytic component of the telomerase ribonucleoprotein complex. We have created a conditionally replicative adenovirus where the viral E1A gene, which is required for viral replication, is under the control of the hTERT promoter (AdhTERTp-E1A). In vitro studies with AdhTERTp-E1A virus on a variety of normal and tumor cell lines have shown that viral genome replication and productive infection is primarily restricted to telomerase-positive tumor cells. Lytic replication was not observed in normal primary fibroblast and epithelial cell lines tested. In vivo administration of the virus into nude mice bearing human liver or prostate tumor xenografts produced significant tumor reduction and, in some cases, resulted in complete tumor regression. AdhTERTp-E1A virus did not actively express E1A in normal mouse liver, in contrast to a control oncolytic vector in which the CMV promoter (AdCMVp-E1A) was driving the E1A gene. In addition, AdhTERTp-E1A virus produced no apparent toxicity to the liver in systemically injected mice. The hTERT promoter-driven oncolytic virus also produced significantly less toxicity to freshly cultured human hepatocytes. These studies demonstrate that an oncolytic virus driven by the telomerase promoter can be used to effectively kill a wide variety of cancer cell types and has the potential to treat primary and metastatic cancer of diverse origins.

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Replication-selective viruses for cancer therapy

Cited by 76 publications

References 95 publications

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells

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

Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity

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