Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter

被引:73
作者
Petrich, T [1 ]
Helmeke, HJ [1 ]
Meyer, GJ [1 ]
Knapp, WH [1 ]
Pötter, E [1 ]
机构
[1] Hannover Med Sch, Dept Nucl Med, D-30625 Hannover, Germany
关键词
sodium/iodide symporter; gene therapy; radioiodine; astatine; cancer;
D O I
10.1007/s00259-002-0784-7
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The sodium/iodide symporter (NIS) has been recognized as an attractive target for radioiodine-mediated cancer gene therapy. In this study we investigated the role of human NIS for cellular uptake of the high LET alpha-emitter astatine-211 (At-211) in comparison with radioiodine as a potential radionuclide for future applications. A mammalian NIS expression vector was constructed and used to generate six stable NIS-expressing cancer cell lines (three derived from thyroid carcinoma, two from colon carcinoma, one from glioblastoma). Compared with the respective control cell lines, steady state radionuclide uptake of NIS-expressing cell lines increased up to 350-fold for iodine-123 (I-123), 340-fold for technetium-99m pertechnetate ((TcO4-)-Tc-99m) and 60-fold for At-211. Cellular At-211 accumulation was found to be dependent on extracellular Na+ ions and displayed a similar sensitivity towards sodium perchlorate inhibition as radioiodide and (TcO4-)-Tc-99m uptake. Heterologous competition with unlabelled NaI decreased NIS-mediated At-211 uptake to levels of NIS-negative control cells. Following uptake both radioiodide and At-211 were rapidly (apparent t(1/2) 3-15 min) released by the cells as determined by wash-out experiments. Data of scintigraphic tumour imaging in a xenograft nude mice model of transplanted NIS-modified thyroid cells indicated that radionuclide uptake in NIS-expressing tumours was up to 70 times (I-123), 25 times ((TcO4-)-Tc-99m) and 10 times (At-211) higher than in control tumours or normal tissues except stomach (3-5 times) and thyroid gland (5-10 times). Thirty-four percent and 14% of the administered activity of I-123 and At-211, respectively, was found in NIS tumours by region of interest analysis (n=2). Compared with cell culture experiments, the effective half-life in vivo was greatly prolonged (6.5 h for I-123, 5.2 h for At-211) and preliminary dosimetric calculations indicate high tumour absorbed doses (3.5 Gy/MBq(tumour) for I-131 and 50.3 Gy/MBq(tumour) for At-211). In conclusion, NIS-expressing tumour cell lines of different origin displayed specific radionuclide uptake in vitro and in vivo. We provide first direct evidence that the high-energy alpha-emitter At-211 is efficiently transported by NIS. Application of At-211 may direct higher radiation doses to experimental tumours than those calculated for I-131. Thus, At-211 may represent a promising alternative radionuclide for future NIS-based tumour therapy.
引用
收藏
页码:842 / 854
页数:13
相关论文
共 57 条
[1]   Iodide symporter gene expression in human thyroid tumors [J].
Arturi, F ;
Russo, D ;
Schlumberger, M ;
du Villard, JA ;
Caillou, B ;
Vigneri, P ;
Wicker, R ;
Chiefari, E ;
Suarez, HG ;
Filetti, S .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1998, 83 (07) :2493-2496
[2]  
BEREI K, 1995, CHEM HALIDES PSEU SD, V2, P787
[3]  
Boland A, 2000, CANCER RES, V60, P3484
[4]   Na+/I- symporter distribution in human thyroid tissues:: An immunohistochemical study [J].
Caillou, B ;
Troalen, F ;
Baudin, E ;
Talbot, M ;
Filetti, S ;
Schlumberger, M ;
Bidart, JM .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1998, 83 (11) :4102-4106
[5]   Experimental targeted radioiodide therapy following transfection of the sodium iodide symporter gene: Effect an clonogenicity in both two-and three-dimensional models [J].
Carlin, S ;
Cunningham, SH ;
Boyd, M ;
McCluskey, AG ;
Mairs, RJ .
CANCER GENE THERAPY, 2000, 7 (12) :1529-1536
[6]   IODIDE TRANSPORT IN THE THYROID-GLAND [J].
CARRASCO, N .
BIOCHIMICA ET BIOPHYSICA ACTA, 1993, 1154 (01) :65-82
[7]   Development of monoclonal antibodies against the human sodium iodide symporter: Immunohistochemical characterization of this protein in thyroid cells [J].
Castro, MR ;
Bergert, ER ;
Beito, TG ;
Mciver, B ;
Goellner, JR ;
Morris, JC .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1999, 84 (08) :2957-2962
[8]   Characterization and radiosensitivity at high or low dose rate of four cell lines derived from human thyroid tumors [J].
Challeton, C ;
Branea, F ;
Schlumberger, M ;
Gaillard, N ;
DeVathaire, F ;
Badie, C ;
Antonini, P ;
Parmentier, C .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 1997, 37 (01) :163-169
[9]   Expression and activity of human Na+/I- symporter in human glioma cells by adenovirus-mediated gene delivery [J].
Cho, JY ;
Xing, S ;
Liu, X ;
Buckwalter, TLF ;
Hwa, L ;
Sferra, TJ ;
Chiu, IM ;
Jhiang, SM .
GENE THERAPY, 2000, 7 (09) :740-749
[10]   TOXICITY OF ASTATINE-211 IN THE MOUSE [J].
COBB, LM ;
HARRISON, A ;
BUTLER, SA .
HUMAN TOXICOLOGY, 1988, 7 (06) :529-534