Adenovirus-mediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma.

Abstract

The present treatment of advanced and metastatic medullary thyroid carcinoma (MTC) is unsatisfactory. Tissue-specific cancer gene therapy is a novel alternative approach. We developed a recombinant adenovirus expressing Herpes simplex type 1 thymidine kinase (HSVtk) driven by a modified CALC-I promoter TCP (AdTCPtk). Infection with this virus showed efficient cytotoxic effect on MTC cell lines (rMTC and TT cells) after treatment with ganciclovir (GCV) in vitro. In a syngenic WAG/Rij rat model, the combination of AdTCPtk/GCV treatment with administration of murine interleukin-12 (mIL-12) expressing adenovirus under control of TCP (AdTCPmIL-12) resulted in effective growth suppression of tumor at the treated site and also at a distant untreated site, in comparison to treatment with AdTCPtk/GCV or AdTCPmIL-12 alone. Moreover, intravenous injection of AdTCPtk, or AdTCPtk+AdTCPmIL-12, followed by administration of GCV, did not cause evident toxicity after administration of GCV. These results indicate that this combined system can provide an effective therapy for metastatic MTC with minimal toxicity.