Background. Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. Methods. Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3(CEA-TK)) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 106 tumor cells consisting of BXPC3 and/or BXPC3(CEA-TK) cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. Results. All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3(CEA-TK) cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3(CEA-TK) engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. Conclusions. These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.
|Original language||English (US)|
|Number of pages||9|
|State||Published - Jan 1 1994|
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