Radionuclide gene therapy with herpes simplex virus type 1 thymidine kinase and I-125 or I-131 labeled nucleoside analog

Objectives The herpes simplex virus type 1 thymidine kinase (HSV1-tk) enzyme selectively phosphorylate and accumulate several nucleoside analogs including 5’-Iodovinyl deoxyuridine (IVDU). This study aims to evaluate whether I-125 or I-131 labeled IVDU has different biological effect in radionuclide gene therapy using HSV1-tk and IVDU.

Methods MCA and MCA-TK cells, retrovirally transduced with HSV1-tk, were used. ¹²⁵I- or ¹³¹I-labeled IVDU uptakes per cell were determined at 4 h incubation in 0, 1, 10 and 100 μCi doses. Radiotherapeutic efficacy of ¹²⁵I- or ¹³¹IVDU (0, 1, 10, 100 μCi) treated MCA and MCA-TK cells for 4 h incubation was evaluated by in vitro clonogenic assay.

Results ¹²⁵IVDU significantly accumulated in MCA-TK cells compared to MCA cells.¹²⁵IVDU or ¹³¹IVDU uptakes in MCA cells were minimal at each radioactivity dose. ¹²⁵IVDU and ¹³¹IVDU uptakes in MCA-TK cells were 9.11±0.03 pCi/cell and 9.19±0.10 pCi/cell, respectively, at 100 mCi dose after 4 h incubation. Survival rate (%) of MCA-TK was markedly decreased as radioactivity dose dependent manner. Survival rate of ¹²⁵IVDU treated MCA-TK(57.02±7.09, 29.88±6.66 and 4.86±4.02) was significantly lower than that of ¹³¹IVDU treated MCA-TK (68.13±7.64, 33.75±2.54 and 20.08±3.65) at 1, 10 and 100 μCi doses.

Conclusions I-125 and I-131 labeled IVDU selectively accumulated and killed HSV1-tk expressing tumor cells. Radionuclide HSV1-tk gene therapy with ¹²⁵IVDU might be better therapeutic strategy than that with ¹³¹IVDU, and further studies is needed for biological mechanism.