title: Sodium iodide symporter (NIS)-mediated radionuclide ((131)I, (188)Re) therapy of liver cancer after transcriptionally targeted intratumoral in vivo NIS gene delivery.
abstract: We reported the therapeutic efficacy of (131)I in hepatocellular carcinoma (HCC) cells stably expressing the sodium iodide symporter (NIS) under the control of the tumor-specific α-fetoprotein (AFP) promoter. In the current study we investigated the efficacy of adenovirus-mediated in vivo NIS gene transfer followed by (131)I and (188)Re administration for the treatment of HCC xenografts. We used a replication-deficient adenovirus carrying the human NIS gene linked to the mouse AFP promoter (Ad5-AFP-NIS) for in vitro and in vivo NIS gene transfer. Functional NIS expression was confirmed by in vivo γ-camera imaging, followed by analysis of NIS protein and mRNA expression. Human HCC (HepG2) cells infected with Ad5-AFP-NIS concentrated 50% of the applied activity of (125)I, which was sufficiently high for a therapeutic effect in an in vitro clonogenic assay. Four days after intratumoral injection of Ad5-AFP-NIS (3×10(9) plaque-forming units) HepG2 xenografts accumulated 14.5% injected dose (ID)/g (123)I with an effective half-life of 13 hr (tumor-absorbed dose, 318 mGy/MBq (131)I). In comparison, 9.2% ID/g (188)Re was accumulated in tumors with an effective half-life of 12.8 hr (tumor-absorbed dose, 545 mGy/MBq). After adenovirus-mediated NIS gene transfer in HepG2 xenografts administration of a therapeutic dose of (131)I or (188)Re (55.5 MBq) resulted in a significant delay in tumor growth and improved survival without a significant difference between (188)Re and (131)I. In conclusion, a therapeutic effect of (131)I and (188)Re was demonstrated in HepG2 xenografts after tumor-specific adenovirus-mediated in vivo NIS gene transfer.
authors.affiliation: Department of Internal Medicine II, Ludwig Maximilians University, Munich 81377, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wunderlich
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.forename: Martina
authors.initials: M
authors.lastname: Anton
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D056945:Hep G2 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011868:Radioisotopes / Q000008:administration & dosage*; D012211:Rhenium / Q000008:administration & dosage*; D027981:Symporters / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D011868:Radioisotopes; D012211:Rhenium; D027981:Symporters; D000099209:Sodium-Iodide Symporters