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Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined  MDR1  shRNA and human  NIS  (hNIS) radioiodine gene therapy in a mouse colon xenograft model.  In vitro  uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed  MDR1  shRNA (Ad-shMDR) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human  NIS  (Ad-hNIS) as compared to control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR and Ad-hNIS infected cells but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was two-fold and 10-fold higher for Ad-shMDR and Ad-hNIS-infected tumors as compared to tumors infected with a control adenovirus construct that expressed [beta]-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have demonstrated successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes.

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Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model