Abstract
The suicide gene and prodrug, herpes simplex thymidine kinase (HStk) and ganciclovir (GCV), are now in clinical trials for recurrent malignancies. We evaluated in vitro and in vivo efficacy of HStk gene transfer and GCV treatment of colonic adenocarcinoma in a syngeneic murine model. In vitro analysis demonstrated that CT-26 adenocarcinoma cells transduced with LTKOSN.2 retroviral vector inhibited the proliferation of wild-type CT-26 (nontransduced) cells after GCV exposure. Cooperative killing with HStk gene therapy was shown in vivo, mixtures of HStk CT-26 transduced cells (CT-26 TK), and nontransduced (CT-26 NV) cells and tumors containing only 9% CT-26 TK cells demonstrated complete regression after GCV (100 mg/kg). This in vitro and in vivo demonstration suggests that metabolic cooperation permits destruction of tumors even when gene transfer is effective only to a relatively small portion of the tumor. These important results suggest new avenues can be developed for the treatment of this lethal malignancy.
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