Document Detail


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
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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:  2014-02-21    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  749-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics*
Adenovirus E1A Proteins / genetics*,  metabolism
Amino Acid Motifs / genetics
Binding Sites / genetics
Cell Line, Tumor
Genetic 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; T32 GM007308/GM/NIGMS 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


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