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Experimental Therapeutics |
Human Gene Therapy Research Institute, Des Moines, Iowa 50309
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The NIS facilitates the accumulation of iodide by thyroid follicular cells to concentrations 20–40-fold over the plasma levels. This is essential for the production of the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3), which are important for growth, development, and metabolism of most tissues (7) . Iodide uptake is competitively inhibited in vitro and in vivo by the anions thiocyanate and perchlorate (7 , 8) . Both the rat and human NIS genes were cloned recently and have been shown to be functional in vitro when expressed in cells from different species (9, 10, 11) .
The cDNA nucleotide sequence of the rat gene (rNIS) contains an open reading frame of 1854 nucleotides that codes for a protein of 618 amino acids with a predicted molecular weight of Mr 65,000 (9) . Secondary structure and hydropathic profile predict an intrinsic membrane protein with 12 membrane-spanning domains (9) . Sequence comparisons to other sodium-dependent cotransporters indicate that the rNIS is most homologous (25% amino acid identity) to the human Na+/glucose cotransporter (9) . Indirect immunofluorescence using a polyclonal anti-COOH terminus antibody in permeabilized FRTL-5 cells confirmed the cytosolic location of the COOH terminus of the rNIS (12) . The cDNA nucleotide sequence of the human gene (hNIS) contains an open reading frame of 1928 nucleotides that codes for a protein of 643 amino acids with an expected molecular weight of Mr 69,000 (11) . The predicted hNIS amino acid sequence has 84% identity and 92% similarity with the rNIS (11) . The hNIS is also predicted to have 12 transmembrane-spanning domains, where the sequences are most highly conserved (11) . Additionally, three charged residues thought to be important for iodide uptake in the rNIS (Asp16, Glu79, and Arg208) are also conserved (9 , 11) .
The iodide-concentrating ability of thyroid cells allows for diagnostic radionuclide thyroid imaging with 123I and 99Tc. Intense radiotherapy of the thyroid using 131I can provide local radiation with minimal (if any) systemic side effects, except the need for thyroid supplements (13) . We demonstrate that retroviral transfer of the rNIS gene into human and murine tumor cells results in highly significant iodide uptake. rNIS-mediated accumulation of 123I or 99Tc by tumors provides a means for diagnostic imaging of solid tumors. Additionally, rNIS-mediated accumulation of 131I is an innovative approach for concentrating a lethal dose of radiation in tumor cells and a new category of gene therapy for cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture and Cell Lines.
Cells were maintained in RPMI 1640 (Life Technologies, Inc.) with 10% fetal bovine serum and 1% penicillin/streptomycin/L-glutamine (Life Technologies, Inc.) at 37°C, 5% CO2. The PA317 packaging cell line was transfected with LNISN and selected in G418 (1 mg/ml) for 14 days (15)
. Supernatants from these cells containing LNISN retroviral particles were used to transduce four cell lines: A375 human melanoma (17)
, BNL.1 ME mouse transformed liver (18)
, CT26 mouse colon carcinoma (19)
, and IGROV human ovarian adenocarcinoma, kindly provided by J. Bernard (20)
. Transduced cells were selected for G418 resistance as described previously (16)
.
Iodide Uptake Experiments.
Both time course and kinetic experiments were performed using the methods of Weiss et al. (21)
. Cells (5 x 104) were seeded into 24-well dishes in 0.5 ml of RPMI 1640. After an 18–24-h incubation period at 37°C with 5.0% CO2, the medium was aspirated, and cells were washed with B-HBSS (Life Technologies, Inc.; Ref. 21
). Iodide uptake was initiated by adding 0.5 ml of B-HBSS containing 0.057–0.345 nM carrier-free Na125I (DuPont NEN) and 5–300 µM NaI to give a specific activity of 88–880 nCi/ml. Incubations (37°C, 5.0% CO2) were performed for 5–120 min. For perchlorate inhibition studies, NaClO4 was added as a 100x solution in B-HBSS, to a final concentration 30 µM, immediately after the addition of radiolabel. Reactions were rapidly terminated by pipetting the radioactive B-HBSS off and washing the cells twice with ice-cold B-HBSS. Cells were then solubilized by incubation for 20 min in 0.4 ml of 1.0% Triton X-100 (Sigma Chemical Co.) in B-HBSS, and accumulated iodide was measured by a Wallac gamma counter. The number of cells/well was determined by harvesting and counting (at the time of the experiment) four additional wells of cells. A 5-min time point was used to estimate initial velocity for kinetics experiments as described (21)
. For kinetics, the average cpm/105 cells of NV cells was subtracted from each cpm/105 cells in each experimental condition.
Iodide Efflux Determinations in FRTL-5 and Tumor Cells.
Cells were plated as described for uptake experiments. Cells were incubated as described above in B-HBSS with 30–100 µM NaI and 0.0575–0.345 nM Na125I (146–880 nCi/ml) for 60 min. The radioactive medium was removed, cells were washed twice with B-HBSS, and 0.5 ml fresh (iodide-free) B-HBSS was applied and incubated as described above. At varying time points, the B-HBSS was removed, and the cells were solubilized in Triton X-100 and analyzed by a gamma counter.
In Vivo Imaging and Quantitation of Accumulated Radionuclides in Explanted rNIS-transduced A375 Human Melanoma Tumors.
Tumors were established in athymic nude mice (Harlan Sprague Dawley, Indianapolis, IN) by intradermal injection of 5 x 106 rNIS-transduced A375 cells on the left ventral hind limb and a similar number of NV tumor cells on the right ventral hind limb. By 30 days after injection, tumors had reached 
10 mm in diameter. Mice were injected i.p. with 0.2 ml of a saline solution containing 8 µCi of 123I (Syncor, Des Moines, IA), which releases 159 KeV gamma energy. Sixty-two min after injection, a 5-min planar image was obtained using a Park Isocam II camera (Park Medical Systems, Montreal, Canada) with a low energy, high resolution collimator. Immediately afterward, the mice were euthanized, and the tumors were carefully dissected and weighed. The amount of 123I accumulated by the tumors was quantitated using a Ludlam model 2200 Scaler Ratemeter and single channel well analyzer (Ludlam Measurements, Inc., Sweetwater, TX).
In Vitro Clonogenic Assays to Demonstrate 131I-mediated Killing of rNIS-transduced Murine and Human Tumors.
Cells were grown to 50% confluence in T80 flasks (Nunc) with RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin/L-glutamine. The cells were then washed with HBSS and allowed to incubate 7 h (5% CO2 at 37°C) after the addition of 10 ml of 100 µCi/ml Na131I (DuPont NEN, Boston, MA) in 30 µM NaI in B-HBSS (21)
. Then each cell line was washed twice with B-HBSS, trypsinized, counted, and plated at densities of 125, 250, and 1000 cells/well in six-well plates in quadruplicate. The cells were placed in 5% CO2 at 37°C for 5–8 days. Then each plate was fixed with 3:1 methanol:acetic acid and stained with crystal violet, the colonies were counted, and the mean and SD were calculated (22)
. Each cell line, NIS-transduced or NV, had cells exposed to 131I (experimental) and cells exposed to only B-HBSS (control). All values were adjusted for plating efficiency before comparisons were made. The percentage of survival represents the percentage of cell colonies after 131I treatment compared with mock treatment with B-HBSS.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Uptake in rNIS-transduced cells is between 8- and 21-fold that observed in nontransduced lines (NV) and 9–35-fold that of lines transduced with the LTKOSN retroviral vector containing the herpes simplex virus thymidine kinase gene (TKO). Additionally, uptake is inhibited 8–11-fold by 30 µM perchlorate, a competitive inhibitor of iodide uptake (7
, 10
, 11
, 21
, 23)
. These results clearly demonstrate rNIS-dependent iodide uptake by the tumor cells. They are consistent with our results obtained with FRTL-5 cells (Fig. 2A)
and data reported previously (9, 10, 11
, 14
, 21)
.
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. Consistent with our results with FRTL-5 cells (Fig. 2B)
, those reported previously (21)
, and results with other NIS-transfected lines (9
, 10)
, the iodide accumulation reaches a steady state within 20–30 min after iodide is added. Furthermore, iodide is rapidly lost from FRTL-5 and rNIS-transduced tumor cells. Iodide efflux was examined by replacing the radioiodide-containing B-HBSS with iodide-free B-HBSS after a 1-h incubation. Accumulated iodide is rapidly lost from the tumor cells (Fig. 4)
and FRTL-5 cells (Fig. 2C
; Refs. 10
and 21
). Efflux still occurred when cells were placed on ice, suggesting a passive process. The saturation kinetics of iodide uptake were determined for FRTL-5 cells and tumor lines (Figs. 1D
and 5
, respectively). The initial velocity of iodide uptake was determined at 5 min in B-HBSS with iodide concentrations of 5–300 µM. Lineweaver-Burk double-reciprocal plots (24)
yield the Km and Vmax values. The calculated Km values (Fig. 2D)
are similar to values reported previously for FRTL-5 cells (9
, 10)
and are also consistent with data from other rNIS-expressing mammalian cell lines (9
, 10) . Our Vmax values are between 23 and 75% of that seen for FRTL-5 cells, which likely indicates that fewer symporter molecules are functional per cell. These results clearly demonstrate that the NIS functions similarly in both tumor cell lines and FRTL-5 cells.
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10 mm in diameter, as seen in Fig. 6A
(30 days after injection), the mice were injected i.p. with 8 µCi of 123I, which approximates the human equivalent dose (for imaging the thyroid) per kg for a 25-g mouse (25)
. Sixty-two min after the isotope was injected, a 5-min planar image of the mouse was obtained (Fig. 6B)
. The image shows in vivo uptake in expected sites including the salivary glands, thyroid, stomach, and bladder. Importantly, the NIS-transduced tumor is readily visible with an intensity similar to the thyroid gland, whereas the nontransduced tumor is not seen. Such results strikingly demonstrate the clear utility of the rNIS gene to image nonthyroid tumors.
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rNIS-transduced Tumor Cells Can Be Selectively Killed with 131I.
A clonogenic assay was used to determine whether rNIS-transduced cells could be selectively killed by treatment with 131I. rNIS-transduced and NV tumor cell lines were exposed to B-HBSS containing 100 µCi/ml 131I (133 nM Na131I) with 30 µM NaI. Control cells were treated in parallel with HBSS without 131I. After 7 h, cells were washed, harvested, and plated at low densities. Colony formation was assessed between 5 and 8 days after plating. Although only 10–17% of the NV cells were killed by exposure to 131I, between 56 and 69% of the rNIS-transduced cells were killed (Fig. 7)
. The results are highly significant for tumor cells growing in a monolayer because a great proportion of the ß energy emitted from accumulated 131I is deposited outside of the monolayer cells. The results demonstrate that rNIS-transduced cell lines are selectively killed by treatment with 131I.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In vivo imaging and ex vivo quantitation experiments indicate that 123I accumulation occurs in rNIS-transduced A375 tumors; these are easily distinguished from nontransduced tumors in vivo (Fig. 6)
. Our results suggest that NIS gene therapy may have applications for in vivo diagnostic imaging. A developing effective and specific means of imaging tumors involves the use of tumor-specific monoclonal antibodies (28)
. However, these are only specific to a relatively limited subset of malignancies including lymphoma, ovarian, prostate, colorectal, and small-cell lung cancer (29)
. Additionally, multiple administrations of mouse antibodies can lead to a human anti-mouse antibody response, which can interfere with localization (30, 31, 32)
and possibly induce allergic responses (33)
. Imaging with the NIS gene using tumor-specific promoters (3
, 4)
will compete with these established antibody approaches when promoter elements can be engineered to achieve a difficult task, high level expression specificity in target tumors."
Efficacy experiments show selective killing of up to 64% of rNIS-transduced tumor cells plated in monolayer after 131I accumulation (Fig. 7)
. The in vitro cell culture methods provide suboptimal conditions to kill cells by rNIS-mediated 131I uptake because most of the ß energy from accumulated iodide is deposited outside of the cell (34)
. The dose from accumulated 131I is affected by cell density, radius, and the stopping power of the ß particle energy emitted by 131I; the absorbed dose can be simplified to the following equation: 
, where µ refers to the stopping power for ß energy (3.009 m2/kg) x cell density (approximately 1.3 x 103 kg/m3) and t is the cell radius in meters (34
, 35)
. The absorbed dose from accumulated 131I increases exponentially as the radius of a tumor mass increases. Thus, a 0.5-mm tumor mass in vivo could receive a significantly higher proportion of the possible ß-energy dose (>90%) from accumulated 131I than our monolayer cells (<4%). Nonetheless, even under these suboptimal conditions, selective rNIS-dependent killing by treatment with 131I is observed (Fig. 7)
. NIS-mediated radioiodide accumulation should be more effective in vivo, because many tumors will have diameters significantly greater than that of monolayer cells.
To further develop the hypothesis that this method will be more effective for cell masses with radii larger than a single cell, we are presently determining 131I efficacy using NIS-transduced tumor spheroids grown in soft agar (36)
and in mice (both of which have substantially larger radii than monolayer cells). Additionally, bystander radiation killing will be an attractive component of this NIS-mediated system because the ß energy from 131I can travel 1.2 mm from the point of radionuclide decay in tissues (35)
. The increased radii of the tumor masses in the tumor spheroid and in vivo systems will allow a greater deposition of energy into neighboring cells. Furthermore, because energy can be effectively deposited in neighboring cells that may not have the rNIS, gene delivery to cells in a tumor mass may not require 100% gene transfer efficiency. Even a conservative interpretation of our results suggests that the NIS gene therapy approach represents a promising method for antitumor radiotherapy. Once the complex issues involving the regulation of NIS expression and/or targeting are addressed, the method could potentially transform any type of malignancy into one as treatable as thyroid cancer. We are examining the use of different promoters and delivery vehicle systems in an effort to increase expression levels of the NIS gene in tumor cells.
Nonthyroid, rNIS-expressing cells do not organify iodide like many thyroid cancers, which means that the concentration of internalized iodide will drop proportionally to the external iodide concentration (Fig. 4)
. Therefore, an important question becomes whether thyroid carcinomas that are effectively treated by 131I therapy can concentrate and/or organify radioiodine. Previous investigators have demonstrated that thyroid carcinoma often has a defect in the ability to accumulate iodide compared with the normal thyroid gland (37
, 38)
. Furthermore, only variable amounts of organification occur within thyroid carcinomas (37
, 39)
. Consistent with these observations, it has been shown recently that whereas NIS mRNA and protein levels are actually increased in some papillary thyroid carcinomas, they concentrate much less iodide than normal thyroid tissue (40)
. Rare cases have been reported where metastatic lesions from thyroid carcinoma lead to a state of thyrotoxicosis from overproduction of tri-iodothyronine or thyroxine (41)
. Such cases where tumors can synthesize thyroid hormones are very unusual (42)
. Therefore, the majority of thyroid carcinomas do not have significant thyroid hormone synthetic ability and hence do not organify normal amounts of iodide. Although the relative amount of iodide organification is much less than normal thyroid tissue, it may still be substantially greater than for other solid neoplasms, such as melanoma and ovarian cancer (as demonstrated in this report). Another key issue is the relative radiosensitivity of the histological type of tumor, which clearly varies among malignant cell types (43)
. Further study on solid tumors in animals will be required to determine the relationship between iodide uptake and efficacy for nonthyroid tumors.
The reduction or elimination of systemic toxicities would represent a substantial gain for patients with recurrent cancer. A variety of efficient gene delivery methods are in development in human clinical trials. (44) Our approach should be adaptable to other gene delivery methods and hopefully will allow the development of human clinical trials using the NIS gene as an antitumor agent. This new tumor-killing strategy should have several significant advantages over present treatment approaches for recurrent, localized cancer lesions. The transition to the clinic should be facilitated by the fact that 131I uptake protocols are already routinely used in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Present address: Molecular Geriatrics Corp., 50 Lakeview Parkway, Suite 111, Vernon Hills, IL 60061. 
2 To whom requests for reprints should be addressed, at Human Gene Therapy Research Institute, 1415 Woodland Avenue, Des Moines, IA 50309. Phone: (515) 241-8787; Fax: (515) 241-8788: E-mail: linkcj{at}ihs.org
3 The abbreviations used are: rNIS and hNIS, rat and human sodium/iodide symporter, respectively; B-HBSS, buffered HBSS; NV, no vector; i.p., intraperitoneal.
Received 7/24/98. Accepted 12/ 1/98.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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L. Zhang, S. Sharma, L. X. Zhu, T. Kogai, J. M. Hershman, G. A. Brent, S. M. Dubinett, and M. Huang Nonradioactive Iodide Effectively Induces Apoptosis in Genetically Modified Lung Cancer Cells Cancer Res., August 15, 2003; 63(16): 5065 - 5072. [Abstract] [Full Text] [PDF]
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C. Spitzweg, I. V. Scholz, E. R. Bergert, D. J. Tindall, C. Y. F. Young, B. Goke, and J. C. Morris Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells Endocrinology, August 1, 2003; 144(8): 3423 - 3432. [Abstract] [Full Text] [PDF]
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M. Braga-Basaria and M. D. Ringel Beyond Radioiodine: A Review of Potential New Therapeutic Approaches for Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1947 - 1960. [Abstract] [Full Text] [PDF]
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I. L. Wapnir, M. van de Rijn, K. Nowels, P. S. Amenta, K. Walton, K. Montgomery, R. S. Greco, O. Dohan, and N. Carrasco Immunohistochemical Profile of the Sodium/Iodide Symporter in Thyroid, Breast, and Other Carcinomas Using High Density Tissue Microarrays and Conventional Sections J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1880 - 1888. [Abstract] [Full Text] [PDF]
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M. L. Schipper, A. Weber, M. Behe, R. Goke, W. Joba, H. Schmidt, T. Bert, B. Simon, R. Arnold, A. E. Heufelder, et al. Radioiodide Treatment after Sodium Iodide Symporter Gene Transfer Is a Highly Effective Therapy in Neuroendocrine Tumor Cells Cancer Res., March 15, 2003; 63(6): 1333 - 1338. [Abstract] [Full Text] [PDF]
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O. Dohan, A. De la Vieja, V. Paroder, C. Riedel, M. Artani, M. Reed, C. S. Ginter, and N. Carrasco The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance Endocr. Rev., February 1, 2003; 24(1): 48 - 77. [Abstract] [Full Text] [PDF]
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J.-K. Chung Sodium Iodide Symporter: Its Role in Nuclear Medicine J. Nucl. Med., September 1, 2002; 43(9): 1188 - 1200. [Abstract] [Full Text] [PDF]
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J. W. A. Smit, J. P. Schroder-van der Elst, M. Karperien, I. Que, M. Stokkel, D. van der Heide, and J. A. Romijn Iodide Kinetics and Experimental 131I Therapy in a Xenotransplanted Human Sodium-Iodide Symporter-Transfected Human Follicular Thyroid Carcinoma Cell Line J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1247 - 1253. [Abstract] [Full Text] [PDF]
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V. Kundra, F. Mannting, A. G. Jones, and A. I. Kassis Noninvasive Monitoring of Somatostatin Receptor Type 2 Chimeric Gene Transfer J. Nucl. Med., March 1, 2002; 43(3): 406 - 412. [Abstract] [Full Text] [PDF]
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 U. Haberkorn and A. Altmann Imaging Techniques for Gene Therapy: SPECT, PET, and MRI Journal of Pharmacy Practice, October 1, 2001; 14(5): 383 - 396. [Abstract] [PDF]
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A. Moore, L. Josephson, R. M. Bhorade, J. P. Basilion, and R. Weissleder Human Transferrin Receptor Gene as a Marker Gene for MR Imaging Radiology, October 1, 2001; 221(1): 244 - 250. [Abstract] [Full Text] [PDF]
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J. P. Schroder-van der Elst, D. van der Heide, J. Kastelijn, B. Rousset, and M. Jesus Obregon The Expression of the Sodium/Iodide Symporter Is Up-Regulated in the Thyroid of Fetuses of Iodine-Deficient Rats Endocrinology, September 1, 2001; 142(9): 3736 - 3741. [Abstract] [Full Text] [PDF]
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C. Nichol and E. E. Kim Molecular Imaging and Gene Therapy J. Nucl. Med., September 1, 2001; 42(9): 1368 - 1374. [Abstract] [Full Text] [PDF]
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O. C. Boerman, W. J.G. Oyen, and F. H.M. Corstens Progress in Gene Therapy: Seeing Is Believing J. Nucl. Med., August 1, 2001; 42(8): 1235 - 1237. [Full Text] [PDF]
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C. Spitzweg, K. J. Harrington, L. A. Pinke, R. G. Vile, and J. C. Morris The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3327 - 3335. [Full Text] [PDF]
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R. Weissleder and U. Mahmood Molecular Imaging Radiology, May 1, 2001; 219(2): 316 - 333. [Abstract] [Full Text]
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U. Haberkorn, M. Henze, A. Altmann, S. Jiang, I. Morr, M. Mahmut, P. Peschke, W. Kübler, J. Debus, and M. Eisenhut Transfer of the Human NaI Symporter Gene Enhances Iodide Uptake in Hepatoma Cells J. Nucl. Med., February 1, 2001; 42(2): 317 - 325. [Abstract] [Full Text]
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J.-L. C. Urbain Reporter Genes and Imagene J. Nucl. Med., January 1, 2001; 42(1): 106 - 109. [Full Text] [PDF]
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C. Spitzweg, M. K. O’Connor, E. R. Bergert, D. J. Tindall, C. Y. F. Young, and J. C. Morris Treatment of Prostate Cancer by Radioiodine Therapy after Tissue-specific Expression of the Sodium Iodide Symporter Cancer Res., November 1, 2000; 60(22): 6526 - 6530. [Abstract] [Full Text]
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Y. Nakamoto, T. Saga, T. Misaki, H. Kobayashi, N. Sato, T. Ishimori, S. Kosugi, H. Sakahara, and J. Konishi Establishment and Characterization of a Breast Cancer Cell Line Expressing Na+/I- Symporters for Radioiodide Concentrator Gene Therapy J. Nucl. Med., November 1, 2000; 41(11): 1898 - 1904. [Abstract] [Full Text] [PDF]
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A. Boland, M. Ricard, P. Opolon, J.-M. Bidart, P. Yeh, S. Filetti, M. Schlumberger, and M. Perricaudet Adenovirus-mediated Transfer of the Thyroid Sodium/Iodide Symporter Gene into Tumors for a Targeted Radiotherapy Cancer Res., July 1, 2000; 60(13): 3484 - 3492. [Abstract] [Full Text]
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 A. De la Vieja, O. Dohan, O. Levy, and N. Carrasco Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology Physiol Rev, July 1, 2000; 80(3): 1083 - 1105. [Abstract] [Full Text] [PDF]
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 T. Kogai, J. J. Schultz, L. S. Johnson, M. Huang, and G. A. Brent Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line PNAS, July 18, 2000; 97(15): 8519 - 8524. [Abstract] [Full Text] [PDF]
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