title: Human sodium iodide symporter added to multidrug resistance 1 small hairpin RNA in a single gene construct enhances the therapeutic effects of radioiodine in a nude mouse model of multidrug resistant colon cancer.
abstract: The objective of this study was to investigate the therapeutic potential of ¹³¹I added to doxorubicin therapy in multidrug resistance (MDR) mouse colon cancer coexpressing the MDR1 small hairpin RNA (shRNA) and human sodium iodide symporter (hNIS) gene in a single gene construct and to visualize the antitumor effects using molecular nuclear imaging. HCT-15 coexpressing shRNA for MDR1 gene (MDR1 shRNA) and hNIS gene with a single construct was established (referred to as MN61 cell). Inhibition of P-gp function by MDR1 shRNA and functional activity of hNIS gene was assessed using a ⁹⁹(m)Tc sestamibi uptake and ¹²⁵I uptake, respectively. Cytotoxic effects by a combination of doxorubicin and ¹³¹I were determined in parental (HCT-15) or MN61 cells using an in vitro clonogenic assay. Therapeutic effect of either combination therapy (doxorubicin and ¹³¹I) or single therapy (doxorubicin or ¹³¹I alone) was evaluated by tumor volume measurement. ⁹⁹(m)Tc-sestamibi, ¹²³I, and ⁹⁹(m)Tc-pertechnetate images of mice were acquired to evaluate functional assessment in vivo. Cellular uptake of ⁹⁹(m)Tc-sestamibi and ¹²⁵I was approximately 2-fold and 100-fold higher in MN61 cells than in parental cells, respectively. Combination of ¹³¹I and doxorubicin resulted in higher cytotoxcity in MN61 cells as compared with parental cells. Scintigraphic imaging showed higher uptake of ⁹⁹(m)Tc-sestamibi and ¹²³I in MN61 tumor as compared with parental tumor. In mice treated with doxorubicin, there was a slight delay in tumor growth in the MN61 tumor but not in the parental tumor. Cancer treatment with ¹³¹I or doxorubicin induced a rapid reduction of tumor volume in the MN61 tumor but not in the parental tumor. Combination therapy further generated a rapid reduction of tumor volume as compared with ¹³¹I therapy alone (p < 0.05). A combination hNIS mediated radioiodine gene therapy added to MDR1 shRNA treatment improved the effects of cancer treatment in a MDR cancer model and could enable visualization of the antitumor effects with nuclear imaging.
authors.affiliation: Department of Nuclear Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Jeon
authors.forename: Sohn Joo
authors.initials: SJ
authors.lastname: Ahn
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: You La
authors.initials: YL
authors.lastname: Lee
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Seung-Yoon
authors.initials: SY
authors.lastname: Park
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.forename: Byeong-Cheol
authors.initials: BC
authors.lastname: Ahn
authors.forename: Jeoung-Hee
authors.initials: JH
authors.lastname: Ha
authors.forename: Jaetae
authors.initials: J
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics* / Q000627:therapeutic use; D011877:Radionuclide Imaging; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017256:Technetium Tc 99m Sestamibi / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D007457:Iodine Radioisotopes; D034741:RNA, Small Interfering; D027981:Symporters; D017256:Technetium Tc 99m Sestamibi; D000099209:Sodium-Iodide Symporters