Noninvasive imaging for evaluation of the systemic delivery of capsid‐modified adenoviruses in an orthotopic model of advanced lung cancer

BACKGROUND. Variable expression of the coxsackie and adenovirus receptor (CAR) has limited gene transfer efficacy to many types of tumors. Consequently, tropism‐modified adenoviruses have been developed for enhanced infectivity. To the authors' knowledge, targeting approaches for nonsmall cell...

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Bibliographic Details
Published in:Cancer 2006-10, Vol.107 (7), p.1578-1588
Main Authors: Sarkioja, Merja, Kanerva, Anna, Salo, Jarmo, Kangasniemi, Lotta, Eriksson, Minna, Raki, Mari, Ranki, Tuuli, Hakkarainen, Tanja, Hemminki, Akseli
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenovirus
Animals
Capsid - chemistry
Capsid - metabolism
Carcinoma, Non-Small-Cell Lung - therapy
Female
Fluorometry
gene therapy
Gene Transfer Techniques
Green Fluorescent Proteins - analysis
Green Fluorescent Proteins - genetics
Humans
in vivo imaging
Lung Neoplasms - therapy
Mice
Mice, Inbred Strains
nonsmall cell lung cancer
Oligopeptides - chemistry
Oncolytic Virotherapy
orthotopic model
Receptors, Virus - metabolism
Virus Replication
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Summary:BACKGROUND. Variable expression of the coxsackie and adenovirus receptor (CAR) has limited gene transfer efficacy to many types of tumors. Consequently, tropism‐modified adenoviruses have been developed for enhanced infectivity. To the authors' knowledge, targeting approaches for nonsmall cell lung cancer (NSCLC) have not been comprehensively evaluated. The current hypothesis was that modified adenoviruses could be used for increasing gene transfer to and killing of NSCLC cells in vitro and in vivo. METHODS. Ten NSCLC cell lines were analyzed to represent the different NSCLC histologies. Because clinical tumors may differ from established cell lines, 6 clinical specimens fresh from patients were analyzed. For in vivo studies, a novel orthotopic murine model of advanced lung cancer was developed. Because tumor response is difficult to quantitate in orthotopic models, noninvasive imaging of green fluorescent protein (GFP) was utilized as a surrogate for tumor size measurements. RESULTS. Adenoviruses whose capsids were modified with RGD‐4C, the serotype 3 knob, or polylysine displayed increased gene transfer to NSCLC cell lines and clinical samples in comparison to serotype 5 viruses. Conditionally replicating oncolytic adenoviruses (CRAds) with the same modifications showed enhanced therapeutic efficiency in vitro and in vivo. The median survival of mice treated with Ad5.pK7‐Δ24 or Ad5‐Δ24RGD increased 37% (P
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.22209