Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy.
The Na+/I- symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with 131I. We propose to enlarge this therapeutic strategy to nonthyroid tumors by using an adenoviral vector to deliver the NIS gene into the tumor cells. We constructed a recombinant adenovirus encoding the rat NIS gene under the control of the cytomegalovirus promoter (AdNIS). Infection of SiHa cells (human cervix tumor cells) with AdNIS resulted in perchlorate-sensitive 125I uptake by these cells to a level 125-225 times higher than that in noninfected cells. Similar results were obtained for other human tumor cell lines, including MCF7 and T-47D (mammary gland), DU 145 and PC-3 (prostate), A549 (lung), and HT-29 (colon), demonstrating that the AdNIS vector can function in tumor cells of various origins. In addition, AdNIS-infected tumor cells were selectively killed by exposure to 131I, as revealed by clonogenic assays. To assess the efficiency of this cancer gene therapy strategy in vivo, we injected the AdNIS vector in human tumors (SiHa or MCF7 cells) established s.c. in nude mice. Immunohistological analysis confirmed the expression of the NIS protein in the tumor. Three days after intratumoral injection, AdNIS-treated tumors could specifically accumulate 125I or 123I, as revealed by kinetics and imaging experiments. A quantitative analysis demonstrated that the uptake in AdNIS-injected tumors was 4-25 times higher than that in nontreated tumors. On average, 11% of the total amount of injected 125I could be recovered per gram of AdNIS-treated tumor tissue. Altogether, these data indicate that AdNIS is very efficient in triggering significant iodide uptake by a tumor, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.
UMR1582 CNRS-IGR-Rhône-Poulenc, Villejuif, France. boland@igr.fr
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A
Boland
M
M
Ricard
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Opolon
J M
JM
Bidart
P
P
Yeh
S
S
Filetti
M
M
Schlumberger
M
M
Perricaudet
D000256:Adenoviridae; D000818:Animals; D001692:Biological Transport; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007454:Iodides / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008175:Lung Neoplasms; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms; D011877:Radionuclide Imaging; D011878:Radiotherapy / Q000379:methods*; D051381:Rats; D027981:Symporters; D013961:Thyroid Gland / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D000099209:Sodium-Iodide Symporters
D002352:Carrier Proteins; D007454:Iodides; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters