Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits

Cichon, Günter; Schmidt, Hartmut; Benhidjeb, Tahar; Löser, Peter; Ziemer, Sabine; Haas, Regina; Grewe, N; Schnieders, Frank; Heeren, J.; Manns, Michael P.; Schlag, Peter M.; Strauß, Michael

doi:10.1002/(sici)1521-2254(199909/10)1:5<360::aid-jgm54>3.0.co;2-q

Cited by 88 publications

(80 citation statements)

References 34 publications

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“…Hematological alterations are also frequently observed after systemic administration of large doses of adenoviruses. 20,23,24 We observed significant thrombocytopenia and lymphopenia after AdwtRGD injection, but not after ICOVIR-7 (Figures 2b and c). In addition, although intravenous AdwtRGD at 5 Â 10 10 viral particles decreased the body weight of mice significantly, indicating high toxicity, ICOVIR-7 at the same dose did not differ from phosphate-buffered saline (PBS) in this regard (Figure 2d).…”

Section: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 80%

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: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 80%

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

et al. 2009

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“…19 In clinical trials for the treatment of malignant tumors 20 or the correction of monogenetic diseases, 1 doses of up to 3 × 10 11 particles per kg body weight have been applied by intravascular application via the hepatic artery. Immediately after virus infusion, the blood or blood plasma, respectively, will contain about about 7.5 × 10 9 viral particles per ml.…”

Section: Discussionmentioning

confidence: 99%

Complement activation by recombinant adenoviruses

et al. 2001

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“…After i.v. injection, it is safe to consider that there is a transient viremia that lasts 48-72 h. Vector diffuses in well-irrigated organs, mainly the liver and lung, 1,31 and also in the spleen and kidneys (see above). In rodents, the liver is clearly the most important target organ (see above).…”

Section: Discussionmentioning

confidence: 99%

“…75 In rodents and lagomorphs, cytokine levels were not investigated to our knowledge, but hematological modifications were evidenced. 1 Carefully and well-designed toxicology studies even in rodents, relying on sound biodistribution, can therefore help predicting vector's fate in humans, as in small molecules. Interestingly, the administration of AdV i.m.…”

Section: Discussionmentioning

confidence: 99%

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Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development

Gonin

Gaillard

2004

Gene Ther

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Techniques allowing for gene transfer vectors biodistribution investigation, in the frame of preclinical gene therapy development, are exposed. Emphasis is given on validation and test performance assessment. In the second part, specific gene vector distribution properties are reviewed (adenovirus, AAV, plasmid, retroviruses, herpes-derived vectors, germline transmission risks). The rationale for biodistribution by quantitative PCR, animal study and result interpretation is discussed. The importance and pivotal role of biodistribution study in gene transfer medicine development is shown through the determination of target organs for toxicity, germline transmission assessment and determination of risks of shedding and spreading of vectors in the gene transfer recipient and the environment.

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Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits

Cited by 88 publications

References 34 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

Complement activation by recombinant adenoviruses

Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development

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