GENE-THERAPY FOR COLON-CANCER WITH THE HERPES-SIMPLEX THYMIDINE KINASE GENE

Background: The suicide gene and prodrug, herpes simplex thymidine kin ase (HStk) and ganciclovir (GCV), are now in clinical trials for recur rent malignancies. Methods: We evaluated in vitro and in vivo efficacy of HStk gene transfer and GCV treatment of colonic adenocarcinoma in a syngeneic murine model. Results: 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 sho wn in vivo, mixtures of HStk CT-26 transduced cells (CT-26 TK), and no ntransduced (CT-26 NV) cells and tumors containing only 9% CT-26 TK ce lls demonstrated complete regression after GCV (100 mg/kg). Conclusion s: This in vitro and in vivo demonstration suggests that metabolic coo peration permits destruction of tumors even when gene transfer is effe ctive only to a relatively small portion of the tumor. These important results suggest new avenues can be developed for the treatment of thi s lethal malignancy. (C) 1997 Wiley-Liss, Inc.