14084
2011
eng
1-14
36
9
article
1
2016-11-25
--
--
Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus
Introduction:
Oncolytic viruses show promise for treating cancer. However, to assess therapeutic efficacy and potential toxicity, a noninvasive imaging modality is needed. This study aimed to determine if insertion of the human sodium iodide symporter (hNIS) cDNA as a marker for non-invasive imaging of virotherapy alters the replication and oncolytic capability of a novel vaccinia virus, GLV-1h153.
Methods:
GLV-1h153 was modified from parental vaccinia virus GLV-1h68 to carry hNIS via homologous recombination. GLV-1h153 was tested against human pancreatic cancer cell line PANC-1 for replication via viral plaque assays and flow cytometry. Expression and transportation of hNIS in infected cells was evaluated using Westernblot and immunofluorescence. Intracellular uptake of radioiodide was assessed using radiouptake assays. Viral cytotoxicity and tumor regression of treated PANC-1tumor xenografts in nude mice was also determined. Finally, tumor radiouptake in xenografts was assessed via positron emission tomography (PET) utilizing carrier-free (124)I radiotracer.
Results:
GLV-1h153 infected, replicated within, and killed PANC-1 cells as efficiently as GLV-1h68. GLV-1h153 provided dose-dependent levels of hNIS expression in infected cells. Immunofluorescence detected transport of the protein to the cell membrane prior to cell lysis, enhancing hNIS-specific radiouptake (P < 0.001). In vivo, GLV-1h153 was as safe and effective as GLV-1h68 in regressing pancreatic cancer xenografts (P < 0.001). Finally, intratumoral injection of GLV-1h153 facilitated imaging of virus replication in tumors via (124)I-PET.
Conclusion:
Insertion of the hNIS gene does not hinder replication or oncolytic capability of GLV-1h153, rendering this novel virus a promising new candidate for the noninvasive imaging and tracking of oncolytic viral therapy.
Journal of Translational Medicine
10.1186/1479-5876-9-36
urn:nbn:de:bvb:20-opus-140847
Journal of Translational Medicine 2011 9:36., doi:10.1186/1479-5876-9-36
Dana Haddad
Nanhai G. Chen
Qian Zhang
Chun-Hao Chen
Yong A. Yu
Lorena Gonzalez
Susanne G. Carpenter
Joshua Carson
Joyce Au
Arjun Mittra
Mithat Gonen
Pat B. Zanzonico
Yuman Fong
Aladar A. Szalay
eng
uncontrolled
Human Sodium/Iodide symporter
eng
uncontrolled
Reporter gene
eng
uncontrolled
NA+/I-symporter
eng
uncontrolled
Nude-mice
eng
uncontrolled
Cancer
eng
uncontrolled
In-Vivo
eng
uncontrolled
Expression
eng
uncontrolled
Therapy
eng
uncontrolled
Transporter
eng
uncontrolled
GLV-1H68
Biochemie
open_access
Lehrstuhl für Biochemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14084/077_Dana_JOURNAL-OF-TRANSLATIONAL-MEDICINE.pdf
13004
2012
eng
e41647
8
7
article
1
2016-03-16
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--
Imaging Characteristics, Tissue Distribution, and Spread of a Novel Oncolytic Vaccinia Virus Carrying the Human Sodium Iodide Symporter
Introduction: Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS.
Methods: GLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide \(^{131}\)I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP) and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via \(^{124}\)I-positron emission tomography (PET). Detection of systemic administration of virus was investigated with both \(^{124}\)I-PET and 99m-technecium gamma-scintigraphy.
Results: GLV-1h153 successfully facilitated time-dependent intracellular uptake of \(^{131}\)I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P < 0.05). In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 10\(^9\) plaque-forming unit (PFU)/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean % ID/gm of 3.82 \(\pm\) 60.46 (P < 0.05) 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV1h153-infected tumors were detected via \(^{124}\)I-PET and 99m-technecium-scintigraphy.
Conclusion: GLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic cancer cells, facilitating detection by PET with both intratumoral and systemic administration. Therefore, GLV-1h153 is a promising candidate for the noninvasive imaging of virotherapy and warrants further study into longterm monitoring of virotherapy and potential radiocombination therapies with this treatment and imaging modality.
PLoS One
10.1371/journal.pone.0041647
urn:nbn:de:bvb:20-opus-130041
PLoS ONE 7(8): e41647. doi:10.1371/journal.pone.0041647
Dana Haddad
Chun-Hao Chen
Sean Carlin
Gerd Silberhumer
Nanhai G. Chen
Qian Zhang
Valerie Longo
Susanne G. Carpenter
Arjun Mittra
Joshua Carson
Joyce Au
Mithat Gonen
Pat B. Zanzonico
Aladar A. Szalay
Yuman Fong
eng
uncontrolled
nude mice
eng
uncontrolled
pancreatic cancer
eng
uncontrolled
engineered measles-virus
eng
uncontrolled
positron-emission-tomography
eng
uncontrolled
malignant pleural mesothelioma
eng
uncontrolled
reporter gene
eng
uncontrolled
replicating adenovirus
eng
uncontrolled
NA/I symporter
eng
uncontrolled
breast cancer
eng
uncontrolled
viral therapy
Medizin und Gesundheit
open_access
Lehrstuhl für Biochemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13004/Haddad_journal.pone.0041647.pdf