Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses

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Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses. / Rojas, JJ; Guedan, S; Searle, Peter; Martinez-Quintanilla, J; Gil-Hoyos, R; Alcayaga-Miranda, F; Cascallo, M; Alemany, R.

In: Molecular Therapy, Vol. 18, No. 11, 01.11.2010, p. 1960-1971.

Research output: Contribution to journalArticle

Harvard

Rojas, JJ, Guedan, S, Searle, P, Martinez-Quintanilla, J, Gil-Hoyos, R, Alcayaga-Miranda, F, Cascallo, M & Alemany, R 2010, 'Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses', Molecular Therapy, vol. 18, no. 11, pp. 1960-1971. https://doi.org/10.1038/mt.2010.173

APA

Rojas, JJ., Guedan, S., Searle, P., Martinez-Quintanilla, J., Gil-Hoyos, R., Alcayaga-Miranda, F., Cascallo, M., & Alemany, R. (2010). Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses. Molecular Therapy, 18(11), 1960-1971. https://doi.org/10.1038/mt.2010.173

Vancouver

Author

Rojas, JJ ; Guedan, S ; Searle, Peter ; Martinez-Quintanilla, J ; Gil-Hoyos, R ; Alcayaga-Miranda, F ; Cascallo, M ; Alemany, R. / Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses. In: Molecular Therapy. 2010 ; Vol. 18, No. 11. pp. 1960-1971.

Bibtex

@article{279d0475a2704f4dbfdbb74a20ae6765,
title = "Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses",
abstract = "Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Delta 24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adeno virus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.",
author = "JJ Rojas and S Guedan and Peter Searle and J Martinez-Quintanilla and R Gil-Hoyos and F Alcayaga-Miranda and M Cascallo and R Alemany",
year = "2010",
month = nov,
day = "1",
doi = "10.1038/mt.2010.173",
language = "English",
volume = "18",
pages = "1960--1971",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "11",

}

RIS

TY - JOUR

T1 - Minimal RB-responsive E1A Promoter Modification to Attain Potency, Selectivity, and Transgene-arming Capacity in Oncolytic Adenoviruses

AU - Rojas, JJ

AU - Guedan, S

AU - Searle, Peter

AU - Martinez-Quintanilla, J

AU - Gil-Hoyos, R

AU - Alcayaga-Miranda, F

AU - Cascallo, M

AU - Alemany, R

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Delta 24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adeno virus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.

AB - Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Delta 24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adeno virus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.

U2 - 10.1038/mt.2010.173

DO - 10.1038/mt.2010.173

M3 - Article

C2 - 20808288

VL - 18

SP - 1960

EP - 1971

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 11

ER -