DRUG-RESISTANCE TO GANCICLOVIR OBSERVED IN SUICIDE GENE-THERAPY IS DUE TO THE LOSS OF INTEGRATED HERPES-SIMPLEX VIRUS-THYMIDINE KINASE GENE

Human pancreatic cancer cells (AsPC-1) expressing the herpes simplex v irus-thymidine kinase (HSV-TK) gene were inoculated into nude mice and ganciclovir (GCV) was administrated for the treatment. At the initial course of treatment we observed a notable reduction of tumor masses. However, therapeutic effect of GCV to the recurrent tumors decreased s ignificantly. This reduced sensitivity of the AsPC-1/HSV-TK cells to G CV was also confirmed by an in vitro test. Examination of HSV-TK gene in the drug resistant cells showed a loss of the integrated gene. Thes e data indicate that repeated GCV administration results in the loss o f integrated HSV-TK gene and confers GCV resistance.