Targeted radionuclide therapy using a Wnt-targeted replicating adenovirus encoding the Na/I symporter.
OBJECTIVE
The Na/I symporter (hNIS) promotes concentration of iodine in cells. In cancer gene therapy, this transgene has potential as a reporter gene for molecular imaging of viral biodistribution and as a therapeutic protein promoting (131)I-mediated radiotherapy. Here, we combined the imaging and therapeutic potential of hNIS in an oncolytic adenoviruses targeting colorectal cancer cells.


METHODS
We generated an adenovirus (AdIP2) encoding hNIS and capable of selective replication in colorectal carcinoma cells. The selectivity of this virus was verified in vitro and in vivo. Its spread in tumors was monitored in vivo using single-photon emission computed tomography/CT imaging upon (99m)TcO(4)(-) injection and confirmed by immunohistochemistry. Metabolic radiotherapy was done through injection of therapeutic doses of (131)I(-).


RESULTS
We showed in vitro and in vivo the selectivity of AdIP2 and that hNIS expression is restricted to the target cells. Imaging and immunohistochemical data showed that viral spread is limited and that the point of maximal hNIS expression is reached 48 hours after a single intratumoral injection. Administration of a single therapeutic dose of (131)I at this time point led to a dramatic reduction in tumor size not observed in hNIS-negative viruses.


CONCLUSIONS
This report showed for the first time that the combination of the imaging and therapeutic potentials of hNIS can be applied to oncolytic adenoviruses in experimental models of cancer.
Peerlinck
Inge
I
Centre for Molecular Oncology, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
Merron
Andrew
A
Baril
Patrick
P
Conchon
Sophie
S
Martin-Duque
Pilar
P
Hindorf
Cécilia
C
Burnet
Jerome
J
Quintanilla
Miguel
M
Hingorani
Mohan
M
Iggo
Richard
R
Lemoine
Nick R
NR
Harrington
Kevin
K
Vassaux
Georges
G
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000628:therapy*; D003952:Diagnostic Imaging; D018390:Gene Targeting; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D011877:Radionuclide Imaging; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D051153:Wnt Proteins / Q000378:metabolism*; D000099209:Sodium-Iodide Symporters
D007457:Iodine Radioisotopes; D027981:Symporters; D051153:Wnt Proteins; D000099209:Sodium-Iodide Symporters