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

Yong Hyun Jeon, Sohn Joo Ahn, Yong Jin Lee, You La Lee, Sang Woo Lee, Seung Yoon Park, In-San Kim, Byeong Cheol Ahn, Jeoung Hee Ha, Jaetae Lee

Research output: Contribution to journalArticle

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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 99mTc 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. 99mTc-sestamibi, 123I, and 99mTc-pertechnetate images of mice were acquired to evaluate functional assessment in vivo. Cellular uptake of 99mTc-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 99mTc-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.

Original languageEnglish
Pages (from-to)671-679
Number of pages9
JournalCancer Biotherapy and Radiopharmaceuticals
Volume25
Issue number6
DOIs
Publication statusPublished - 2010 Dec 1
Externally publishedYes

Fingerprint

Multiple Drug Resistance
Therapeutic Uses
Nude Mice
Colonic Neoplasms
Small Interfering RNA
Doxorubicin
Technetium Tc 99m Sestamibi
Genes
Neoplasms
Tumor Burden
Therapeutics
sodium-iodide symporter
Sodium Pertechnetate Tc 99m
Molecular Imaging
Human Activities
Genetic Therapy

Keywords

  • I
  • Combination therapy
  • doxorubicin
  • MDR1
  • NIS
  • P-gp
  • shRNA

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology
  • Cancer Research

Cite this

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. / Jeon, Yong Hyun; Ahn, Sohn Joo; Lee, Yong Jin; Lee, You La; Lee, Sang Woo; Park, Seung Yoon; Kim, In-San; Ahn, Byeong Cheol; Ha, Jeoung Hee; Lee, Jaetae.

In: Cancer Biotherapy and Radiopharmaceuticals, Vol. 25, No. 6, 01.12.2010, p. 671-679.

Research output: Contribution to journalArticle

Jeon, Yong Hyun ; Ahn, Sohn Joo ; Lee, Yong Jin ; Lee, You La ; Lee, Sang Woo ; Park, Seung Yoon ; Kim, In-San ; Ahn, Byeong Cheol ; Ha, Jeoung Hee ; Lee, Jaetae. / 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. In: Cancer Biotherapy and Radiopharmaceuticals. 2010 ; Vol. 25, No. 6. pp. 671-679.
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