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.

摘要

The objective of this study was to investigate the therapeutic potential of (1)(3)(1)I 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 (m)Tc sestamibi uptake and (1)(2)I uptake, respectively. Cytotoxic effects by a combination of doxorubicin and (1)(3)(1)I were determined in parental (HCT-15) or MN61 cells using an in vitro clonogenic assay. Therapeutic effect of either combination therapy (doxorubicin and (1)(3)(1)I) or single therapy (doxorubicin or (1)(3)(1)I alone) was evaluated by tumor volume measurement. (m)Tc-sestamibi, (1)(2)(3)I, and (m)Tc-pertechnetate images of mice were acquired to evaluate functional assessment in vivo. Cellular uptake of (m)Tc-sestamibi and (1)(2)I was approximately 2-fold and 100-fold higher in MN61 cells than in parental cells, respectively. Combination of (1)(3)(1)I and doxorubicin resulted in higher cytotoxcity in MN61 cells as compared with parental cells. Scintigraphic imaging showed higher uptake of (m)Tc-sestamibi and (1)(2)(3)I 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 (1)(3)(1)I 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 (1)(3)(1)I 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.