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.
Centre for Molecular Oncology, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
Inge
I
Peerlinck
Andrew
A
Merron
Patrick
P
Baril
Sophie
S
Conchon
Pilar
P
Martin-Duque
Cécilia
C
Hindorf
Jerome
J
Burnet
Miguel
M
Quintanilla
Mohan
M
Hingorani
Richard
R
Iggo
Nick R
NR
Lemoine
Kevin
K
Harrington
Georges
G
Vassaux
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