ADENOVIRAL-MEDIATED DELIVERY OF THE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE SELECTIVELY SENSITIZES HUMAN OVARIAN-CARCINOMA CELLS TO GANCICLOVIR

One strategy used for gene therapy of cancer is molecular chemotherapy . This approach is based on selective expression of an encoded toxin i n cancer cells to achieve their eradication, One potential advantage o f this strategy derives from a phenomenon, termed the bystander effect , whereby only a fraction of cells needs to be transduced to eradicate a tumor population, Despite the theoretical advantages of this phenom enon, it has only been described in a few cellular targets, Therefore, we undertook strategies to develop a molecular chemotherapy approach for ovarian carcinoma utilizing the herpes simplex virus thymidine kin ase (HSV-TK) gene, Initially, we established that human ovarian carcin oma cell lines could be transduced at high efficiency with adenoviral vectors encoding reporter genes, We next determined that the human ova rian cell line SKOV3 could exhibit bystander killing by stably transdu cing it to express HSV-TK and performing cell mixing experiments with varying percentages of HSV-TK-expressing and HSV-TK-nonexpressing cell s, Based on these findings, we constructed a recombinant adenovirus en coding HSV-TK and utilized it to induce human ovarian carcinoma cell l ines to the sensitizing effects of ganciclovir, In addition, primary c ultures of ovarian carcinoma cells were found to be highly transducibl e with recombinant adenoviral vectors and could be induced to the sens itizing effects of ganciclovir after induction of HSV-TK expression by the adenoviral vector, These studies indicate that molecular chemothe rapy using a recombinant adenoviral vector expressing HSV-TK may provi de a rational strategy for human ovarian carcinoma.