Enhanced iodide transport after transfer of the human sodium iodide symporter gene is associated with lack of retention and low absorbed dose

Haberkorn, Uwe; Kinscherf, Ralf; Kissel, Maria; Kübler, W; Mahmut, Miriam; Sieger, Stephanie; Eisenhut, Michael; Peschke, Peter; Altmann, Annette

doi:10.1038/sj.gt.3301943

Cited by 41 publications

(31 citation statements)

References 33 publications

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“…Therefore, induction of NIS expression in cancer cells to deliver radioiodine is currently being explored for many types of extra-thyroid neoplasia (Hingorani et al 2010). While encouraging results have been obtained in some preclinical models, unresolved issues are still present about the feasibility of a gene therapy-based approach in humans (Haberkorn et al 2003). Equally promising are the attempts to stimulate endogenous NIS expression in those tumor cells, from thyroid and non-thyroid cancers, with detectable levels of NIS mRNA (Kogai et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas

Micali

Maggisano²,

Cesinaro³

et al. 2012

Journal of Endocrinology

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Testicular cancer is the most frequent cancer in young men. The large majority of patients have a good prognosis, but in a small group of tumors, the current treatments are not effective. Radioiodine is routinely used in the treatment of thyroid cancer and is currently investigated as a potential therapeutic tool even for extra-thyroid tumors able to concentrate this radioisotope. Expression of Na C /I K symporter (NIS (SLC5A5)), the glycoprotein responsible for iodide transport, has been demonstrated in normal testicular tissue. In this study, we analyzed NIS expression in a large series of testicular carcinomas. Our retrospective series included 107 patients operated for testicular tumors: 98 typical seminomas, six embryonal carcinomas, one mixed embryonal choriocarcinoma, and two Leydig cells tumors. Expression and regulation of NIS mRNA and protein levels were also investigated in human embryonal testicular carcinoma cells (NTERA) by real-time RT-PCR and western blotting respectively. Immunohistochemical analysis showed the presence of NIS in the large majority of seminomas (90/98) and embryonal carcinomas (5/7) of the testis but not in Leydig cell carcinomas. Expression of NIS protein was significantly associated with lymphovascular invasion. In NTERA cells treated with the histone deacetylase inhibitors SAHA and valproic acid, a significant increase in NIS mRNA (about 60-and 30-fold vs control, P!0.001 and P!0.01 respectively) and protein levels, resulting in enhanced ability to uptake radioiodine, was observed. Finally, NIS expression in testicular tumors with the more aggressive behavior is of interest for the potential use of targeting NIS to deliver radioiodine in malignant cells.

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Section: Discussionmentioning

confidence: 99%

Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas

Micali

Maggisano²,

Cesinaro³

et al. 2012

Journal of Endocrinology

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“…Although the tumors efficiently concentrated iodide after NIS gene transfer, no effect of 131 I on tumor growth was observed because the rapid iodide efflux from the tumor did not allow the delivery of a radiation dose sufficient to inhibit cell growth. 21,31,32 Thus, to efficiently therapy tumor with 131 I by gene transfer, it is mandatory to increase the retention time of iodide in the tumor. An appealing strategy is to mimic the situation existing in the thyroid, that is, to organify the iodide taken up by the tumor.…”

Section: Discussionmentioning

confidence: 99%

Combining transfer of TTF-1 and Pax-8 gene: a potential strategy to promote radioiodine therapy of thyroid carcinoma

Huang

et al. 2012

Cancer Gene Ther

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Cotransfer of thyroid-specific transcription factor (TTF)-1 and Pax-8 gene to tumor cells, resulting in the re-expression of iodide metabolism-associated proteins, such as sodium iodide symporter (NIS), thyroglobulin (Tg), thyroperoxidase (TPO), offers the possibility of radioiodine therapy to non-iodide-concentrating tumor because the expression of iodide metabolism-associated proteins in thyroid are mediated by the thyroid transcription factor TTF-1 and Pax-8. The human TTF-1 and Pax-8 gene were transducted into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus, AdTTF-1 and AdPax-8. Re-expression of NIS mRNA and protein, but not TPO and Tg mRNA and protein, was detected in AdTTF-1-infected F133 cells, following with increasing radioiodine uptake (6.1 --7.4 times), scarcely iodide organification and rapid iodide efflux (t 1/2 E8-min in vitro, t 1/2 E4.7-h in vivo). On contrast, all of the re-expression of NIS, TPO and Tg mRNA and proteins were detected in F133 cells coinfected with AdTTF-1 and AdPax-8. AdTTF-1-and AdPax-8-coinfected K1 and F133 cells could effectively accumulate radioiodine (6.6 --7.5 times) and obviously retarded radioiodine retention (t 1/2 E25 --30-min in vitro, t 1/2 E12-h in vivo) (Po0.05). Accordingly, the effect of radioiodine therapy of TTF-1 and Pax-8 cotransducted K1 and F133 cells (21 --25% survival rate in vitro) was better than that of TTF-1-transducted cells (40% survival rate in vitro) (Po0.05). These results indicate that single TTF-1 gene transfer may have limited efficacy of radioiodine therapy because of rapid radioiodine efflux. The cotransduction of TTF-1 and Pax-8 gene, with resulting NISmediated radioiodine accumulation and TPO and Tg-mediated radioiodine organification and intracellular retention, may lead to effective radioiodine therapy of thyroid carcinoma.

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“…Prolonged retention of iodide observed in vivo was not attributed to an active retention mechanism, but to permanent recycling of the effluent radioiodine via the high hepatic blood flow. Ra-dioiodine therapy in these circumstances was associated with strong inhibition of tumour growth, complete regression of small nodules and prolonged survival of hepatocarcinoma-bearing rats [142]. Gaut et al (2004) reported on a study of NIS-mediated radioiodide therapy in a head and neck cancer model.…”

Section: Preclinical Studies Of Nis Gene Transfer By Replication-defementioning

confidence: 99%

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

Hingorani¹

2010

CCDT

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The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic ( 99m Tc, 125 I, 124 I) and therapeutic ( 131 I, 186 Re, 188 Re, 211 At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.

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Enhanced iodide transport after transfer of the human sodium iodide symporter gene is associated with lack of retention and low absorbed dose

Cited by 41 publications

References 33 publications

Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas

Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas

Combining transfer of TTF-1 and Pax-8 gene: a potential strategy to promote radioiodine therapy of thyroid carcinoma

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

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