hTPO和hNIS共转染胶质瘤细胞介导放射性碘治疗的实验研究
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摘要
目的:构建含有人甲状腺过氧化物酶基因(hTPO)的重组腺病毒AdTPO,并将AdTPO和人钠碘转运体基因(hNIS)分别转入胶质瘤细胞系U251中,获得稳定表达hTPO和hNIS基因的细胞系hNIS-AdTPO-U251和hNIS-U251,在(125)~I的作用下研究细胞的摄碘能力及摄碘时间。
方法:克隆,重组,包装并扩增纯化得到重组腺病毒(AdTPO),并且测定病毒滴度,Western-Blotting检测重组腺病毒的表达。鉴定已构建好的重组质粒(pcDNA3.1-hNIS)。使用脂质体转染法将hNIS基因转染入人胶质瘤细胞系U251中,经过G418抗生素筛选获得稳定表达hNIS的细胞系,为阴性对照组(hNIS-U251);使用重组腺病毒将hTPO基因转导入U251中,使胶质瘤细胞获得hTPO基因,为实验组(AdTPO—hNIS-U251)。未转入hTPO和hNIS的细胞为空白对照组(U251)。进行感染后稳定表达细胞系的体外摄(125)~I实验,体外(125)~I外流实验,体外(125)~I内流实验,过氯酸盐抑制实验,(125)~I有机化测定试验,细胞克隆形成实验等。
结果:
1.hNIS在U251细胞中有瞬时表达,转染了hNIS的U251细胞比未转染hNIS的空白组摄(125)~I能力增高约4倍左右(P＜0.01)。
2.通过重组腺病毒感染已经稳定表达hNIS基因的U251细胞系,将hTPO基因转导至U251细胞后,hNIS联合AdTPO共转染组与空白对照组的摄(125)~I能力相比增高约147倍左右(P＜0.01),hNIS单独转染组与空白对照组的摄碘能力相比增高约110倍(P＜0.01)。
3.(125)~I内流的动态演变实验证实(125)~I在实验组和阴性对照组稳定表达细胞系中均快速聚集,约90-120min时达到稳定阶段。
4.(125)~I外流的动态演变实验证实阴性对照组中(125)~I的有效半衰期为7min,实验组的(125)~I外流减慢,其有效半衰期延长至13min。
5.NaClO_4抑制试验表明加入NaClO_4的实验组和阴性对照组的摄(125)~I能力明显受到抑制,摄碘能力均降低30倍左右(P＜0.001)。
6.(125)~I有机化测定试验证实hNIS和hTPO共转染U251细胞的有机化程度高于单独hNIS转染U251细胞。
7.细胞克隆实验表明经(131)~I孵育后实验组比未经(131)~I孵育的空白对照组的克滦纬陕视兴档?P＜0.01),约降低13倍左右;经(131)~I孵育后阴性对照组比未经(131)~I孵育的空白对照组的克隆形成率有所降低(P＜0.01),约降低10倍左右;而未经(131)~I孵育的实验组与阴性对照组及空白对照组的细胞克隆形成率相比未见明显差异。
结论:成功获得高滴度的重组腺病毒AdTPO。将hTPO基因和hNIS基因共转染至胶质瘤细胞系U251后,实验组摄碘能力有明显增高,可以部分有机化碘,有效半衰期延长至13min,可以延长放射性碘在细胞中的停留时间。
Objective:To construct the recombinant hTPO gene with adenvirus and transfer hTPO and hNIS genes into U251 cell line.Stably expressing hTPO and hNIS gene cell line (AdTPO-hNIS-U251) and stably expressing hNIS gene cell line(hNIS-U251) were produced.To study the iodide uptake ablibities and effective half lives of iodide in the above cell lines.
Methods:Through cloning,recombination,packaging and amplifying,the recombinant adenosine virus AdTPO was constructed.After purification,the viral titers were calculated.Then by using Western-Blotting,the protein expression of AdTPO was tested.We accessed the recombinant plasmids pcDNA3.1- hNIS.After transecting hNIS gene into human glioma cell line U251 through liposome,stably expressing hNIS gene cell line(hNIS-U251) selected by G418 antibiotics was determined as the negative control groups.By using adenosine virus,hTPO was transducted into hNIS-U251,which was used as the testing group (AdTPO-hNIS-U251).U251 cell without any plasmids was applied as blank control group(U251).Then,we investigated biologic functions of the above cells,including ~(125)I uptake assay,~(125)I influx-course test,~(125)I effiux-course test,perchlorate suppressive assay,~(125)I organification degree assay and cell clonogenic assay.
Results:
1.The uptake ability of ~(125)I was 4 fold higher in hNIS-U251 cells than in blank control U251 cells(P＜0.01).
2.The uptake ability of ~(125)I was 147 fold higher in AdTPO-hNIS-U251 cells than in blank control U251 cells(P＜0.01),and 110 fold higher in hNIS-U251 cells than in blank control U251 cells(P＜0.01).
3.~(125)I influx test showed:~(125)I accumulated quickly in negative control group and in testing group,and reached the steady state with 90-120min after iodide was added. The blank control group couldn't accumulate ~(125)I.
4.~(125)I effiux test showed:The effiux of ~(125)I was rapid in negative control group,its effective half life was about 7 min,the effective half life was prolonged to 13 min in testing group.
5.Perchlorate suppressive assay showed:Uptake was inhibited by NaClO_4 in AdTPO-hNIS-U251 cells and hNIS-U251 cells.
6.~(125)I organification degree assay:In testing group,the ~(125)I organifi- cation degree was higher than the groups without AdTPO.
7.Cell clonogenic assays demonstrated the clonal forming efficiency of testing group after incubating with ~(131)I was 13 fold lower than the group which was not incubated with ~(131)I(P＜0.01).And the clonal forming efficiency of negative control group after incubating was 10 fold lower than the group which was not incubated with ~(131)I(P＜0.01).The clonal forming efficiecies of all three groups without incubation with ~(131)I showed no significant difference.
Conclusion:High titer AdTPO was constructed by using convenient Adeasier Systerm. Co-transfection with hNIS and hTPO genes could increase iodide uptake and radioiodide organification,which could prolong T_(1/2) effiux to 13min and increase retention of radioiodide in the cell.
方法:克隆,重组,包装并扩增纯化得到重组腺病毒(AdTPO),并且测定病毒滴度,Western-Blotting检测重组腺病毒的表达。鉴定已构建好的重组质粒(pcDNA3.1-hNIS)。使用脂质体转染法将hNIS基因转染入人胶质瘤细胞系U251中,经过G418抗生素筛选获得稳定表达hNIS的细胞系,为阴性对照组(hNIS-U251);使用重组腺病毒将hTPO基因转导入U251中,使胶质瘤细胞获得hTPO基因,为实验组(AdTPO—hNIS-U251)。未转入hTPO和hNIS的细胞为空白对照组(U251)。进行感染后稳定表达细胞系的体外摄(125)~I实验,体外(125)~I外流实验,体外(125)~I内流实验,过氯酸盐抑制实验,(125)~I有机化测定试验,细胞克隆形成实验等。
结果:
1.hNIS在U251细胞中有瞬时表达,转染了hNIS的U251细胞比未转染hNIS的空白组摄(125)~I能力增高约4倍左右(P＜0.01)。
2.通过重组腺病毒感染已经稳定表达hNIS基因的U251细胞系,将hTPO基因转导至U251细胞后,hNIS联合AdTPO共转染组与空白对照组的摄(125)~I能力相比增高约147倍左右(P＜0.01),hNIS单独转染组与空白对照组的摄碘能力相比增高约110倍(P＜0.01)。
3.(125)~I内流的动态演变实验证实(125)~I在实验组和阴性对照组稳定表达细胞系中均快速聚集,约90-120min时达到稳定阶段。
4.(125)~I外流的动态演变实验证实阴性对照组中(125)~I的有效半衰期为7min,实验组的(125)~I外流减慢,其有效半衰期延长至13min。
5.NaClO_4抑制试验表明加入NaClO_4的实验组和阴性对照组的摄(125)~I能力明显受到抑制,摄碘能力均降低30倍左右(P＜0.001)。
6.(125)~I有机化测定试验证实hNIS和hTPO共转染U251细胞的有机化程度高于单独hNIS转染U251细胞。
7.细胞克隆实验表明经(131)~I孵育后实验组比未经(131)~I孵育的空白对照组的克滦纬陕视兴档?P＜0.01),约降低13倍左右;经(131)~I孵育后阴性对照组比未经(131)~I孵育的空白对照组的克隆形成率有所降低(P＜0.01),约降低10倍左右;而未经(131)~I孵育的实验组与阴性对照组及空白对照组的细胞克隆形成率相比未见明显差异。
结论:成功获得高滴度的重组腺病毒AdTPO。将hTPO基因和hNIS基因共转染至胶质瘤细胞系U251后,实验组摄碘能力有明显增高,可以部分有机化碘,有效半衰期延长至13min,可以延长放射性碘在细胞中的停留时间。
Objective:To construct the recombinant hTPO gene with adenvirus and transfer hTPO and hNIS genes into U251 cell line.Stably expressing hTPO and hNIS gene cell line (AdTPO-hNIS-U251) and stably expressing hNIS gene cell line(hNIS-U251) were produced.To study the iodide uptake ablibities and effective half lives of iodide in the above cell lines.
Methods:Through cloning,recombination,packaging and amplifying,the recombinant adenosine virus AdTPO was constructed.After purification,the viral titers were calculated.Then by using Western-Blotting,the protein expression of AdTPO was tested.We accessed the recombinant plasmids pcDNA3.1- hNIS.After transecting hNIS gene into human glioma cell line U251 through liposome,stably expressing hNIS gene cell line(hNIS-U251) selected by G418 antibiotics was determined as the negative control groups.By using adenosine virus,hTPO was transducted into hNIS-U251,which was used as the testing group (AdTPO-hNIS-U251).U251 cell without any plasmids was applied as blank control group(U251).Then,we investigated biologic functions of the above cells,including ~(125)I uptake assay,~(125)I influx-course test,~(125)I effiux-course test,perchlorate suppressive assay,~(125)I organification degree assay and cell clonogenic assay.
Results:
1.The uptake ability of ~(125)I was 4 fold higher in hNIS-U251 cells than in blank control U251 cells(P＜0.01).
2.The uptake ability of ~(125)I was 147 fold higher in AdTPO-hNIS-U251 cells than in blank control U251 cells(P＜0.01),and 110 fold higher in hNIS-U251 cells than in blank control U251 cells(P＜0.01).
3.~(125)I influx test showed:~(125)I accumulated quickly in negative control group and in testing group,and reached the steady state with 90-120min after iodide was added. The blank control group couldn't accumulate ~(125)I.
4.~(125)I effiux test showed:The effiux of ~(125)I was rapid in negative control group,its effective half life was about 7 min,the effective half life was prolonged to 13 min in testing group.
5.Perchlorate suppressive assay showed:Uptake was inhibited by NaClO_4 in AdTPO-hNIS-U251 cells and hNIS-U251 cells.
6.~(125)I organification degree assay:In testing group,the ~(125)I organifi- cation degree was higher than the groups without AdTPO.
7.Cell clonogenic assays demonstrated the clonal forming efficiency of testing group after incubating with ~(131)I was 13 fold lower than the group which was not incubated with ~(131)I(P＜0.01).And the clonal forming efficiency of negative control group after incubating was 10 fold lower than the group which was not incubated with ~(131)I(P＜0.01).The clonal forming efficiecies of all three groups without incubation with ~(131)I showed no significant difference.
Conclusion:High titer AdTPO was constructed by using convenient Adeasier Systerm. Co-transfection with hNIS and hTPO genes could increase iodide uptake and radioiodide organification,which could prolong T_(1/2) effiux to 13min and increase retention of radioiodide in the cell.
引文
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7.Ajjan RA,Kamaruddin NA,Crisp M,et al.Regulation and tissue distribution of the human-sodium iodide symporter gene[J].Clin Endocrinol,1998,49:517-523.
8.Carrasco N.Iodide transport in the thyroid gland[J].Biochim Biophys Acta,1993,1154:65-82.
9.Dohan O,De la Vieja A,Carrasco N.Molecular study of the sodium-iodide symporter (NIS):a new field in thyroidology[J].Trends Endocrinol Metab,2000,11:99-105.
10.Wolff J,Chaikoff IL.Plasma inorganic iodide as a homeostatic bregulator of thyroid function[J].J Biol Chem,1948,174:555-564.
11.Brown-Grant K.Extra thyroidal iodide concentrating mechaNISms[J].Physiol Rev,1961,41:189-213.
12.Smanik PA,Ryu KY,Theil KS,et al.Expression,exon-intron organization,and chromosome mapping of the human sodium iodide symporter[J].Endocrinology,1997,138:3555-3558.
13.Perron B,Rodriguez AM,Leblanc G,et al.Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues[J].J Endocrinol,2001,170:185-196.
14.Cho JY,Leveille R,Kao R,et al.Hormonal regulation of radioiodide uptake activity and Na+/I~-symporter expression in mammary glands[J].J Clin Endocrinol Metab,2000,85:2936-2943.
15.Spitzweg C,Dutton CM,Castro MR et al.Expression of the sodium iodide symporter in human kidney[J].Kidney Int 200159:1013-1023.
16.Lacroix L,Mian C,Caillou B,et al.Na~+/I~-symporter and pendred syndrome gene and protein expressions in human extra-thyroidal tissues[J].Eur J Endocrinol,2001,144:297-302.
17.Mazzaferri EL,Kloos RT.Current approaches to primary therapy for papillary and follicular thyroid cancer[J].J Clin Endocrinol Metab 2001,86:1447-1463.
18.Schlumberger MJ.Papillary and follicular thyroid carcinoma[J].N Engl J Med 1998,338:297-306.
19.Doha'n O,Baloch Z,Banrevi Z,et al.Rapid communication:predominant intracellular overexpression of the Na~+/I~- symporter(NIS) in a large sampling of thyroid cancer cases[J].J Clin Endocrinol Metab,2001,86:2697-2700.
20.Kogai T,Taki K,Brent GA.Enhancement of sodium/iodide symporter expression in thyroid and breast cancer[J].Endocr Relat Cancer,2006,13(3):797-826.
21.Venkataraman GM,Yatin M,Marcinek R,et al.Restoration of iodide uptake in dedifferentiated thyroid carcinoma:relationship to human Na~+/I~-symporter gene methylation status[J].J Clin Endocrinol Metab,1999,84:2449-2457.
22.Schmutzler C,Winzer R,Meissner-Weigl J,et al.Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells[J].Biochem Biophys Res Commun,1997,240:832-838
23.张兰胜.全反式维甲酸对甲状腺癌细胞NIS基因表达及吸碘能力影响的实验研[J].现代肿瘤学,2007,15(7):904-906.
24.KitazonoM,Robery R,Zhan Z,et al.Low concentrations of the histone deacetylase inhibitor,dep sipep tide(FR901228),increase expression of the Na~+/I~-symp torter and iodide accumulation in poorly differentiated thyroid carcinoma celIs [J].J CIin EndocrinolMetab,2001,86:3430-3435.
25.Zarnegar R,Bmnancl L,Kanancaii H,et al.Increasing the efectiveness of radioacaivc iodine Iherapy in the treatment of thyroid cancer using Tricaioslalin A,a histone deacetylase inhibitor[J].Surgery,2002,132(6):984-990.
26.Patel A,Jhiang S,Dogra S,et al.Differentiated thyroid carcinoma that exp ress sodiumiodide symporter have a lower risk of recurrence for children and adolescents [J].Pediatr Res.2002,52:737-744.
27.Cengic N,Baker CH,Sch(u|¨)tz M,et al.A novel therapeutic strategy for medullary thyroid cncer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression[J].J Clin Endocrinol Metab,2005,90(8):4457-4464.
28.Furuya F,Shimura H,Miyazaki A,et al.Adenovirus-mediated transfer of thyroid transcription factor-1 induces radioiodide organification and retention in thyroid cancer cells[J].Endocrinology,2004,145(11):5397-5404.
29.Elisei R,Vivaldi A,Ciampi R,et al.Treatment with drugs able to reduce iodine effiux significantly increases the intracellular retention time in thyroid cancer cells stably transfected with sodium iodide symporter complementary deoxyribonucleic acid[J].J Clin Endocrinol Metab,2006,91(6):2389-2395.
30.Tazebay UH,Wapnir IL,Levy O,et al.The mammary gland iodide transporter is expressed during lactation and in breast cancer[J].Nat Med,2000,6:871-878
31.Kogai T,Schultz JJ,Johnson LS,et al.Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line[J].Proc Natl Acad Sci USA,2000 97:8519-8524
32.Smit JW,Schroder-van der Elst JP,Karperien M,et al.Reestablishment of vitro and in vivo iodide up take by transfection of the human sodium iodide symporter (hN IS) in a hNIS defective human thyroid carcinoma cell line[J].Thyroid,2000,10:939-943.
33.Boland A,Ricard M.Adenovirus mediated transfer of the thyroid Na~+/I~-symporter nene into tumors for a tarneted radiotherapy[J].Cancer Res,2000,60:3484-3492.
34.Mandel RB,Mandel LZ,Link CJJr.Radioisotope concen.trator gene therapy using the sodium/iodide symporter[J].Cancer Res,1999,59 (3):661-668.
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36.Shimura H,Haraguchi K,Miyazaki A,et al.Iodide up take and expe riment ~(131)I therapy in transp lanted undiferentiated thyroid cancer cells exp ressing theNa ~+/I~-symporter gene[J].Endocrinology,1997,138 (10):4493-4496.
37.Smit JW,Schroder-vander Elst JP,KarperienM,et al.Iodide kinetics and experimental I therapy in a xenotransp lanted human sodium-iodide symportertransfected human folicular thyroid carcinoma cell line[J].J Clin Endocrinol Metab,2002,87 (3):1247-1253.
38.Spitzweg C,Connor MK,Bergert ER,et al.Treatment of prostate cancer by radioiodine therapy'after tissues-specific exp ression of sodium / iodide symporter[J].Cancer Res,2000,60:6526-6530.
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40.Dwyer RM,Schatz SM,Bergert ER,et al.A preclinical large animal model of adenovirus-mediated expression of the sodium-iodide symporter for radioiodide imaging and therapy of locally recurrent prostate cancer[J].Mol Ther,2005,12(5):835-841.
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1.SPitzweg C,Joba W,Eiseuntenger W,et al.Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland,mammary glnad,and gastric mucosa[J].J Clin Endocrinol Metab,1998,83(5):1746-1751.
2.Dai QLevy 0,Carrssco N.Cloning and characterization of the thyroid iodide transporter[J].Nature,1996,379(6564):458-460.
3.Smanik AP,Liu Q,Furminger TL,et al.Cloning of the human sodium Iodide symporter[J].Biochem Biophys Res Commun,1996,226(2):339-345.
4.Levy O,De la Vieja A,et al.N-linked glycosylation of the thyroid Na+/I-symporter (NIS).Implications for its secondary structure model[J].J Biol Chem,1998,273(35):22657-22663.
5.Eskandari S,Loo DD,Dai G,et al.Thyroid Na~+/I~-symporter.MechaNISm,stoichiometry,and specificity[J].J Biol Chem,1997,272 (43):27230-27238.
6.Spitzweg C,Heufelder AE,Morris JC.Thyroid iodine transport[J].Thyroid,2000,10 (4):321-330.
7.Ajjan RA,Kamaruddin NA,Crisp M,et al.Regulation and tissue distribution of the human-sodium iodide symporter gene[J].Clin Endocrinol,1998,49:517-523.
8.Carrasco N.Iodide transport in the thyroid gland[J].Biochim Biophys Acta,1993,1154:65-82.
9.Dohan O,De la Vieja A,Carrasco N.Molecular study of the sodium-iodide symporter (NIS):a new field in thyroidology[J].Trends Endocrinol Metab,2000,11:99-105.
10.Wolff J,Chaikoff IL.Plasma inorganic iodide as a homeostatic bregulator of thyroid function[J].J Biol Chem,1948,174:555-564.
11.Brown-Grant K.Extra thyroidal iodide concentrating mechaNISms[J].Physiol Rev,1961,41:189-213.
12.Smanik PA,Ryu KY,Theil KS,et al.Expression,exon-intron organization,and chromosome mapping of the human sodium iodide symporter[J].Endocrinology,1997,138:3555-3558.
13.Perron B,Rodriguez AM,Leblanc G,et al.Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues[J].J Endocrinol,2001,170:185-196.
14.Cho JY,Leveille R,Kao R,et al.Hormonal regulation of radioiodide uptake activity and Na+/I~-symporter expression in mammary glands[J].J Clin Endocrinol Metab,2000,85:2936-2943.
15.Spitzweg C,Dutton CM,Castro MR et al.Expression of the sodium iodide symporter in human kidney[J].Kidney Int 200159:1013-1023.
16.Lacroix L,Mian C,Caillou B,et al.Na~+/I~-symporter and pendred syndrome gene and protein expressions in human extra-thyroidal tissues[J].Eur J Endocrinol,2001,144:297-302.
17.Mazzaferri EL,Kloos RT.Current approaches to primary therapy for papillary and follicular thyroid cancer[J].J Clin Endocrinol Metab 2001,86:1447-1463.
18.Schlumberger MJ.Papillary and follicular thyroid carcinoma[J].N Engl J Med 1998,338:297-306.
19.Doha'n O,Baloch Z,Banrevi Z,et al.Rapid communication:predominant intracellular overexpression of the Na~+/I~- symporter(NIS) in a large sampling of thyroid cancer cases[J].J Clin Endocrinol Metab,2001,86:2697-2700.
20.Kogai T,Taki K,Brent GA.Enhancement of sodium/iodide symporter expression in thyroid and breast cancer[J].Endocr Relat Cancer,2006,13(3):797-826.
21.Venkataraman GM,Yatin M,Marcinek R,et al.Restoration of iodide uptake in dedifferentiated thyroid carcinoma:relationship to human Na~+/I~-symporter gene methylation status[J].J Clin Endocrinol Metab,1999,84:2449-2457.
22.Schmutzler C,Winzer R,Meissner-Weigl J,et al.Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells[J].Biochem Biophys Res Commun,1997,240:832-838
23.张兰胜.全反式维甲酸对甲状腺癌细胞NIS基因表达及吸碘能力影响的实验研[J].现代肿瘤学,2007,15(7):904-906.
24.KitazonoM,Robery R,Zhan Z,et al.Low concentrations of the histone deacetylase inhibitor,dep sipep tide(FR901228),increase expression of the Na~+/I~-symp torter and iodide accumulation in poorly differentiated thyroid carcinoma celIs [J].J CIin EndocrinolMetab,2001,86:3430-3435.
25.Zarnegar R,Bmnancl L,Kanancaii H,et al.Increasing the efectiveness of radioacaivc iodine Iherapy in the treatment of thyroid cancer using Tricaioslalin A,a histone deacetylase inhibitor[J].Surgery,2002,132(6):984-990.
26.Patel A,Jhiang S,Dogra S,et al.Differentiated thyroid carcinoma that exp ress sodiumiodide symporter have a lower risk of recurrence for children and adolescents [J].Pediatr Res.2002,52:737-744.
27.Cengic N,Baker CH,Sch(u|¨)tz M,et al.A novel therapeutic strategy for medullary thyroid cncer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression[J].J Clin Endocrinol Metab,2005,90(8):4457-4464.
28.Furuya F,Shimura H,Miyazaki A,et al.Adenovirus-mediated transfer of thyroid transcription factor-1 induces radioiodide organification and retention in thyroid cancer cells[J].Endocrinology,2004,145(11):5397-5404.
29.Elisei R,Vivaldi A,Ciampi R,et al.Treatment with drugs able to reduce iodine effiux significantly increases the intracellular retention time in thyroid cancer cells stably transfected with sodium iodide symporter complementary deoxyribonucleic acid[J].J Clin Endocrinol Metab,2006,91(6):2389-2395.
30.Tazebay UH,Wapnir IL,Levy O,et al.The mammary gland iodide transporter is expressed during lactation and in breast cancer[J].Nat Med,2000,6:871-878
31.Kogai T,Schultz JJ,Johnson LS,et al.Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line[J].Proc Natl Acad Sci USA,2000 97:8519-8524
32.Smit JW,Schroder-van der Elst JP,Karperien M,et al.Reestablishment of vitro and in vivo iodide up take by transfection of the human sodium iodide symporter (hN IS) in a hNIS defective human thyroid carcinoma cell line[J].Thyroid,2000,10:939-943.
33.Boland A,Ricard M.Adenovirus mediated transfer of the thyroid Na~+/I~-symporter nene into tumors for a tarneted radiotherapy[J].Cancer Res,2000,60:3484-3492.
34.Mandel RB,Mandel LZ,Link CJJr.Radioisotope concen.trator gene therapy using the sodium/iodide symporter[J].Cancer Res,1999,59 (3):661-668.
35.Dohan O,De la Vieja A,ParoderV,et al.The sodium/iodide symporter (NIS):characterization,regulation,and medical significance[J].Endocr Rev,2003,24:48-77.
36.Shimura H,Haraguchi K,Miyazaki A,et al.Iodide up take and expe riment ~(131)I therapy in transp lanted undiferentiated thyroid cancer cells exp ressing theNa ~+/I~-symporter gene[J].Endocrinology,1997,138 (10):4493-4496.
37.Smit JW,Schroder-vander Elst JP,KarperienM,et al.Iodide kinetics and experimental I therapy in a xenotransp lanted human sodium-iodide symportertransfected human folicular thyroid carcinoma cell line[J].J Clin Endocrinol Metab,2002,87 (3):1247-1253.
38.Spitzweg C,Connor MK,Bergert ER,et al.Treatment of prostate cancer by radioiodine therapy'after tissues-specific exp ression of sodium / iodide symporter[J].Cancer Res,2000,60:6526-6530.
39.Dingli D,Kemp BJ,O' Connor MK,et al.Combined I positron emission tomography/computed tomography imaging of NIS gene expression in animal models of stably transfected and intravenously transfected tumor[J].Mol ImagingBiol,2006,8(1):16-23.
40.Dwyer RM,Schatz SM,Bergert ER,et al.A preclinical large animal model of adenovirus-mediated expression of the sodium-iodide symporter for radioiodide imaging and therapy of locally recurrent prostate cancer[J].Mol Ther,2005,12(5):835-841.