Abstract/Details

Sindbis viral vectors as efficient agents for systemic detection and treatment of cancer in animal models


2005 2005

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Abstract (summary)

Successful cancer gene therapy requires a vector that systemically and specifically targets tumor cells throughout the body. Vectors based on Sindbis virus, an alphavirus transmitted by mosquitoes, have several unique features that make them promising agents for successful cancer gene therapy. First, Sindbis vectors infect mammalian cells via the high affinity laminin receptors (LAMR), which are expressed at higher levels in several human cancers than in most normal cells. Immunohistochemical staining of tumor cells indicates that LAMR is elevated in tumor vs. normal cells and a single treatment allows the vectors to target most tumor cells without infecting normal cells. Down-regulated expression of LAMR with siRNA significantly reduces the infectivity of Sindbis vectors. Second, Sindbis vectors are natural blood-borne vectors capable of systemic tumor targeting in vivo. Immunohistochemistry studies indicated that vector infection is associated with tumor vascular structures and suggested a vector delivery pathway via the bloodstream. In addition, systemic vector targeting of tumors growing subcutaneously (s.c.), intrapancreatically, intraperitoneally (i.p.), and in the lungs was observed using the IVIS ® Imaging System that detects bioluminescent signals resulting from vector infection. The vectors are also capable of systemically targeting syngeneic and spontaneous tumors in immune competent animals. Third, Sindbis vectors induce apoptosis in tumors after infection. Tumors from Sindbis treated mice contained more apoptotic cells than control tumors as indicated by TUNEL staining. In some cases, repetitive Sindbis treatments induced complete tumor regression. Fourth, Sindbis vectors can efficiently express transgene payload after infection. By carrying proper transgenes, such as anti-tumor cytokine (IL-12 or IL-15), Sindbis vectors demonstrated enhanced anti-tumor efficacy. In addition, the ability to efficiently express HSVtk suicide gene renders Sindbis vector an ideal vector for gene-directed enzyme/prodrug therapy (GDEPT) for cancer. High levels of HSVtk expression ensures not only sufficient prodrug ganciclovir activation for tumor eradication, but also provides a means for non-invasive imaging of HSVtk activity using positron emission tomography (PET) which might significantly improve the dosing for prodrug treatments.

Indexing (details)


Subject
Microbiology;
Molecular biology
Classification
0410: Microbiology
0307: Molecular biology
Identifier / keyword
Biological sciences; Cancer; Gene therapy; Laminin; Sindbis virus
Title
Sindbis viral vectors as efficient agents for systemic detection and treatment of cancer in animal models
Author
Tseng, Jen-Chieh
Number of pages
153
Publication year
2005
Degree date
2005
School code
0146
Source
DAI-B 66/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542072727, 0542072726
Advisor
Meruelo, Daniel
University/institution
New York University
University location
United States -- New York
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3170885
ProQuest document ID
305469367
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305469367
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