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.
- Combination therapy
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging
- Cancer Research