VIRAL VECTOR TRANSDUCTION OF THE HUMAN DEOXYCYTIDINE KINASE CDNA SENSITIZES GLIOMA-CELLS TO THE CYTOTOXIC EFFECTS OF CYTOSINE-ARABINOSIDE IN-VITRO AND IN-VIVO

Cytosine arabinoside (ara-C) is a cytidine analog that incorporates in to replicating DNA and induces lethal DNA strand breaks. Although ara- C is a potent antitumor agent for hematologic malignancies, it has onl y minimal activity against most solid tumors. The rate-limiting step i n intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cell lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment o f established intradermal and intracerebral gliomas transduced with dC K results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gen e therapy.