Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-α

Engler, Heidrun; Machemer, Todd; Philopena, Jennifer; Wen, Shu-Fen; Quijano, Erlinda; Ramachandra, Murali; Tsai, Van; Ralston, Robert

doi:10.1016/j.virol.2004.06.043

Cited by 48 publications

(36 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even replication-defective Ad or Ad virus components induced toxic responses in the host. Acute induction of proinflammatory cytokines such as IL-6, IL-1β and TNF-α and elevated serum transaminases are common findings following Ad therapy [7,11,12,16,22,37,48]. These responses are presumably due to interactions of Ad or its components with macrophages and liver Kupffer cells [49].…”

Section: Discussionmentioning

confidence: 99%

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

Singh

Prasuhn

Yeh

et al. 2007

Journal of Controlled Release

231

224

View full text Add to dashboard Cite

Virus-based nanoparticles (VNPs) from a variety of sources are being developed for biomedical and nanotechnology applications that include tissue targeting and drug delivery. However, the fate of most of those particles in vivo has not been investigated. Cowpea mosaic virus (CPMV), a plant comovirus, has been found to be amenable to the attachment of a variety of molecules to its coat protein, as well as to modification of the coat protein sequence by genetic means. We report here the results of studies of the bio-distribution, toxicology, and pathology of CPMV in mice. Plasma clearance and tissue biodistribution were measured using CPMV particles derivatized with lanthanide metal complexes. CPMV particles were cleared rapidly from plasma, falling to undetectable levels within 20 minutes. By 30 minutes the majority of the injected VNPs were trapped in the liver and to a lesser extent the spleen with undetectable amounts in other tissues. At doses of 1 mg, 10 mg and 100 mg per kg body weight, no toxicity was noted and the mice appeared to be normal. Hematology was essentially normal, although with the highest dose examined, the mice were somewhat leukopenic with relative decreases in both neutrophils and lymphocytes. Histological examination of spleen showed cellular infiltration, which upon flow cytometry analyses revealed elevated B lymphocytes on the first day following virus administration that subsequently subsided. Microscopic evaluation of various other tissues revealed a lack of apparent tissue degeneration or necrosis. Overall, CPMV appears to be a safe and non-toxic platform for in vivo biomedical applications.

show abstract

Section: Discussionmentioning

confidence: 99%

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

Singh

Prasuhn

Yeh

et al. 2007

Journal of Controlled Release

231

224

View full text Add to dashboard Cite

show abstract

“…34 Despite this inability to release E2F, hepatic toxicity is observed when this virus is injected systemically, as E1A transcription is not regulated and takes place in normal cells. 18 For the systemic treatment of disseminated cancer, E1A transcription control is required. In this regard, the E2F-1 promoter has previously been used to direct E1A transcription in response to Rb pathway deregulation.…”

Section: Discussionmentioning

confidence: 99%

“…18 Strong immunostaining was detected throughout livers from AdwtRGD-treated mice. In contrast, even at the highest dose of ICOVIR-7 (1 Â 10 11 viral particles per mouse), little E1A was detected, indicating that the E2F-responsive promoter effectively restricts the expression of E1A in liver (Figure 3a).…”

Section: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 95%

“…ICOV-IR-7 is a novel oncolytic adenovirus designed to increase selective replication in tumor cells by placing this modified E2F-responsive promoter to control E1A-D24 transcription. As E1A expression determines toxicity, 18 a stricter control of E1A transcription may allow the systemic administration of oncolytic adenoviruses for the treatment of disseminated neoplasias. Figure 1a represents how genetic modifications of ICOVIR-7 work together to abrogate replication in normal cells.…”

Section: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2009

View full text Add to dashboard Cite

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.

show abstract

“…It has previously been shown that TNF-␣ is likely to be involved in host responses to Ad vectors in vitro and in vivo (34). Recently, Shayakhmetov et al (35) have reported that IL-1 signaling, not TNF-␣ signaling, is involved in Ad vector-associated liver toxicity after i.v.…”

Section: Elimination Of Il-6 Signaling Reduces Liver Toxicitymentioning

confidence: 99%

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.

show abstract

Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-α

Cited by 48 publications

References 60 publications

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

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

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Contact Info

Product

Resources

About