Rat sodium iodide symporter allows using lower dose of 131I for cancer therapy

Mitrofanova, Elena; Unfer, Robert C.; Vahanian, Nick; Link, Charles J.

doi:10.1038/sj.gt.3302758

Cited by 22 publications

(18 citation statements)

References 25 publications

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“…Furthermore, cells transfected with rNIS could uptake more radionuclide than hNIS. A number of previous studies showed that rNIS gene expression consistently yielded higher radioiodine uptake levels in every tested cell line, allowing using lower doses of 131 I for gene therapy [11,20,23]. However, there were some differences in the regulation mechanisms between the human and rat genes, as well as in the predicted hydrophilic and hydrophobic regions of the protein structure and in the orientation within the cellular membrane [11,20,23].…”

Section: Discussionmentioning

confidence: 91%

“…However, the main problem was to induce tumor cells to uptake and express the NIS gene. Presently, a number of different viral vectors were used in clinical trials because of their high efficiency, simple preparation, high recombinant virus titer and large heterologous gene segments [20]. A previous study showed the feasibility of using baculovirus to transfect NIS into A549 cells [21].…”

Section: Discussionmentioning

confidence: 99%

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Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

et al. 2015

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The sodium/iodide symporter (NIS) is involved in iodide uptake and has been used for the diagnosis and treatment of thyroid cancer. Transfection of the NIS gene in A549 human lung cancer cells can induce radioactive iodine ((131)I) and radioactive technetium ((99m)Tc) uptake. The aim of the present study was to assess the role of NIS in (99m)Tc and (131)I uptake by the A549/DDP human cisplatin-resistant lung cancer cell line. To do so, recombinant adenovirus, adenovirus-enhanced green fluorescent protein-human NIS (Ad-eGFP-hNIS) and Ad-eGFP-rat NIS (Ad-eGFP-rNIS) vectors were established. These vectors were transfected into A549/DDP cells and xenograft tumors in nude mice. Assessment of (99m)Tc and (131)I uptake was performed. Results showed that the transfection efficiency of Ad-eGFP-hNIS and Ad-eGFP-rNIS in A549/DDP cells was at least 90 % in all experiments, and that the uptake ability of (99m)Tc and (131)I was highly enhanced (14-18 folds for (99m)Tc, and 12-16 folds for (131)I). However, the radionuclide concentration in transfected NIS genes' A549/DDP cells reached a plateau within 30-60 min, indicating that NIS transport led rapidly to (99m)Tc and (131)I saturation in cells. In xenograft tumor models, uptake of (99m)TcO4 (-) was obviously higher in the hNIS and rNIS groups compared with controls. In conclusion, these results support the hypothesis that A549/DDP cells can effectively uptake (99m)Tc and (131)I when transfected with the hNIS and rNIS gene. The rNIS or hNIS gene could be used as an effective method for the effective delivery of radioactive products to specific tissues for imagery and/or treatment.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

et al. 2015

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“…Three-dimensional spheroids have been thus used with NIS radioiodide approach to assess therapeutic efficacy. 54,55 Tumor deposits in orthotopic myeloma models are typically very small (up to 2-mm diameter) even when the disease is far advanced. For this reason we focused our studies initially on mice bearing subcutaneous myeloma tumors with diameters of approximately 5mm.…”

Section: Radioiodide Imaging 2347mentioning

confidence: 99%

Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Δ51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene

Goel¹,

Carlson²,

Classic

et al. 2007

Blood

118

117

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Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(⌬51) - IntroductionMultiple myeloma is a malignancy of antibody-secreting plasma cells that reside predominantly in bone and bone marrow and secrete a monoclonal immunoglobulin. 1 The disease responds initially to alkylating agents, corticosteroids, and thalidomide, but eventually becomes refractory. 2 Multiple myeloma remains incurable causing more than 10 000 deaths each year in the United States. 3 Although cultured myeloma cells are relatively resistant to radiotherapy in vitro, 4,5 the malignancy is highly radiosensitive and radiation therapy is routinely used for palliation of pain, neurologic compromise, or structural instability from focal myeloma deposits. Efforts to use radiation as a systemic modality for definitive therapy of myeloma, however, have been problematic because of collateral toxicity to normal tissues especially the bone marrow progenitor cells. 6,7 Developing novel therapies for multiple myeloma based on the targeted delivery of radioisotopes to sites of active disease may have important clinical implications for myeloma therapy.Gene transfer using the thyroidal sodium iodide symporter (NIS) gene offers a novel strategy for delivery of radionuclides to disseminated cancer cells. 8 NIS is a transmembrane protein in thyroid follicular cells that actively mediates iodide uptake to a concentration gradient more than 20 to 40-fold. 9 Cloning the human NIS cDNA has aided in imaging and therapy of dedifferentiated thyroid cancer and nonthyroid cancers such as glioma, neuroblastoma, melanoma, multiple myeloma, and ovarian, breast, cervix, lung, liver, and colon carcinoma. 10 Tissue-specific NIS expression has been achieved in various cancer xenografts with minimal toxicity to normal organs by using promoters and enhancers from genes encoding immunoglobulins, prostate-specific antigen, probasin, and mucin-1. [11][12][13][14][15][16] Cancer therapy using oncolytic viruses (oncolytic virotherapy) requires agents that amplify efficiently through replication and spread causing rapid tumor lysis, yet are safe causing minimal toxicity to normal tissue enabling systemic inoculations to treat metastatic cancers. 17,18 We previously engineered the NIS gene into a lymphotropic, replication-competent attenuated strain of measles virus (MV-NIS) 19 that was subsequently used for oncolytic virotherapy of myeloma xenografts. Intratumoral spread of MV-NIS could be monitored noninvasively by radioiodine imaging and virus-resistant tumors were ablated after administration of 131 I. 20 A phase I clinical trial to evaluate the targeting properties of MV-NIS in patients with recurrent or refractory myeloma is ongoing at our institution. Several RNA viruses other than measles virus, including reovirus, Newcastle disease virus, mumps virus, and vesicular stomatitis virus (VSV), are being developed as systemic oncolytic agents for cancer therapy. 18,21 Each of these viruses ...

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“…Heltemes et al (2003) reported that the rat NIS protein is more efficient than the human protein for radioisotope concentration. More recently, Mitrofanova et al (2006) compared the human and rat NIS genes for their efficacy in cancer therapy. The authors demonstrated that the rat NIS allows the administration of lower doses of 131 I to arrest the growth of tumor xenografts in mice.…”

Section: Introductionmentioning

confidence: 99%

Comparison of expressed human and mouse sodium/iodide symporters reveals differences in transport properties and subcellular localization

Dayem¹,

Basquin²,

Navarro³

et al. 2008

Journal of Endocrinology

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The active transport of iodide from the bloodstream into thyroid follicular cells is mediated by the Na C /I K symporter (NIS). We studied mouse NIS (mNIS) and found that it catalyzes iodide transport into transfected cells more efficiently than human NIS (hNIS). To further characterize this difference, we compared 125 I uptake in the transiently transfected human embryonic kidney (HEK) 293 cells. We found that the V max for mNIS was four times higher than that for hNIS, and that the iodide transport constant (K m ) was 2 . 5-fold lower for hNIS than mNIS. We also performed immunocytolocalization studies and observed that the subcellular distribution of the two orthologs differed. While the mouse protein was predominantly found at the plasma membrane, its human ortholog was intracellular in w40% of the expressing cells. Using cell surface protein-labeling assays, we found that the plasma membrane localization frequency of the mouse protein was only 2 . 5-fold higher than that of the human protein, and therefore cannot alone account for the difference in the obtained V max values. We reasoned that the observed difference could also be caused by a higher turnover number for iodide transport in the mouse protein.We then expressed and analyzed chimeric proteins. The data obtained with these constructs suggest that the iodide recognition site could be located in the region extending from the N-terminus to transmembrane domain 8, and that the region between transmembrane domain 5 and the C-terminus could play a role in the subcellular localization of the protein.

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Rat sodium iodide symporter allows using lower dose of 131I for cancer therapy

Cited by 22 publications

References 25 publications

Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Δ51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene

Comparison of expressed human and mouse sodium/iodide symporters reveals differences in transport properties and subcellular localization

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