| Impact of E1a modifications on tumor-selective adenoviral replication and toxicity. | |
| | |
MedLine Citation:
|
PMID: 15451459 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Replicating adenoviral vectors are capable of multiplying up to a thousandfold in the target cell, a property that might prove to be of tremendous potential for cancer therapy. However, restricting viral replication and toxicity to cancer cells is essential to optimize safety. It has been proposed that modifications of the E1a protein that impair binding to Rb or p300 will prevent S-phase induction in normal cells, resulting in selective viral replication in tumor cells. However, it remains uncertain which of the several possible E1a modifications would be most effective at protecting normal cells without compromising the oncolytic effect of the vector. In this study, we have expressed several E1a-deletion mutants at high levels using the CMV promoter and tested them for their ability to facilitate S-phase induction, viral replication, and cytotoxicity in both normal and cancer cells. Deletion of the Rb-binding domain within E1a only slightly decreased the ability of the virus to induce S phase in growth-arrested cells. The effect of this deletion on viral replication and cytotoxicity was variable. There was reduced cytotoxicity in normal bronchial epithelial cells; however, in some normal cell types there was equal viral replication and cytotoxicity compared with wild type. Deletions in both the N-terminus and the Rb-binding domain were required to block S-phase induction effectively in growth-arrested normal cells; in addition, this virus demonstrated reduced viral replication and cytotoxicity in normal cells. An equally favorable replication and cytotoxicity profile was induced by a virus expressing E1a that is incapable of binding to the transcriptional adapter motif (TRAM) of p300. All viruses were equally cytotoxic to cancer cells compared with wild-type virus. In conclusion, deletion of the Rb-binding site alone within E1a may not be the most efficacious means of targeting viral replication and toxicity. However, deletion within the N-terminus in conjunction with a deletion within the Rb-binding domain, or deletion of the p300-TRAM binding domain, induces a more favorable cytotoxicity profile. |
| | |
Authors:
|
Harald Sauthoff; Teona Pipiya; Sheila Heitner; Shu Chen; Bertram Bleck; Joan Reibman; William Chang; Robert G Norman; William N Rom; John G Hay |
Related Documents
:
|
15383559 - Rapid response of marginal zone b cells to viral particles. 18987339 - Recql5 plays an important role in dna replication and cell survival after camptothecin ... 20551679 - A dilemma for viruses and giant viruses: which endocytic pathway to use to enter cells? 9499049 - Identification of a domain within the human t-cell leukemia virus type 2 envelope requi... 8709289 - A gene transfer vector-cell line system for complete functional complementation of aden... 16820319 - Interactions of human retroviruses with the host cell cytoskeleton. 20691649 - Lyophilized somatic cells direct embryonic development after whole cell intracytoplasmi... 23389369 - Different methods of detaching adherent cells significantly affect the detection of tra... 22357359 - Catalytic activity of baker's yeast in a mediatorless microbial fuel cell. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: 10 ISSN: 1525-0016 ISO Abbreviation: Mol. Ther. Publication Date: 2004 Oct |
Date Detail:
|
Created Date: 2004-09-28 Completed Date: 2005-04-25 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
|
Languages: eng Pagination: 749-57 Citation Subset: IM |
Affiliation:
|
Division of Pulmonary & Critical Care Medicine, New York University School of Medicine, New York, NY 10016, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adenoviridae
/
genetics* Adenovirus E1A Proteins / genetics*, metabolism Amino Acid Motifs / genetics Binding Sites / genetics Cell Line, Tumor Gene Therapy / methods* Genetic Vectors / toxicity* Humans Immunoprecipitation Neoplasms / therapy* Nuclear Proteins / metabolism Protein Structure, Tertiary / genetics Retinoblastoma Protein / genetics, metabolism S Phase Sequence Deletion Trans-Activators / metabolism Virus Replication / genetics* |
| Grant Support | |
ID/Acronym/Agency:
|
M01RR-00096/RR/NCRR NIH HHS; R01CA102053/CA/NCI NIH HHS; R01CA89086/CA/NCI NIH HHS; R01ES10187/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Adenovirus E1A Proteins; 0/Nuclear Proteins; 0/Retinoblastoma Protein; 0/Trans-Activators |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Human-compatible collagen matrix for prolonged and reversible systemic delivery of erythropoietin in...
Next Document: The human SCGB2A2 (mammaglobin-1) promoter/enhancer in a helper-dependent adenovirus vector directs ...