ADENOVIRUS-MEDIATED GENE-THERAPY OF HEPATOCELLULAR-CARCINOMA USING CANCER SPECIFIC GENE-EXPRESSION

Most patients with hepatocellular carcinoma have an elevated alpha-fet oprotein (AFP) level. This high level of AFP expression is transcripti onally controlled by the 5'-flanking sequence of the AFP gene. Using t he 5'-flanking sequence as a promoter for the herpes simplex virus thy midine kinase (RSV-TK) gene in an adenoviral vector (Av1AFPTK1), the t herapeutic efficacy of adenovirus-mediated HSV-TK gene transduction, f ollowed by ganciclovir (GCV) administration, was studied in tumors in athymic nude mice. Av1AFPTK1 transduction of two cell lines demonstr a ted HSV-TK enzyme activity only in the AFP-producing cells (HuH7) and not in the AFP nonproducing cells (SR-Hep-l). As expected, only transd uced HuH7 cells were killed by GCV treatment. Transduction by an adeno viral vector harboring a Rous sarcoma virus promoter and HSV-TK gene ( Av1TK1) showed enzymatic activity and GCV killing in both cell lines. All HuH7 tumors that were transduced with either Av1AFPTK1 or Av1TK1 c ompletely regressed after GCV treatment. On the other hand, there was complete regression of SK-Hep-l tumors only when treated with Av1TK1 a nd GCV and not when treated with Av1AFPTK1 and GCV. Thus, cell-specifi c killing was achieved by adenoviral vector containing AFP promoter fo r the HSV-TR gene and GCV treatment.