PRODRUG-ACTIVATING GENE THERAPY FOR EXPERIMENTAL GLIOMAS USING THE ESCHERICHIA COLI GPT GENE AND 6-THIOXANTHINE.

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A recently described strategy for the tretment of brain tumors involves the trasfer and expression of an exogenous prodrug-activating gene into the neoplastic cell, thereby rendering it capable to convert an inactive agent into an oncolytic metabolite. A gene/drug combination employs the Esherichia coli gpt gene, which encodes xanthine-guanine phosphoribosyl transferase (XGPRT) and can convert the inactive prodrug, such as 6-thioxanthine (6-TX), into the toxic metabolites.In the present study, we have investigated the usefulness of the 6-TX/gpt gene therapy paradigm for gliomas. Our in vitro results show that the prodrug, 6-TX successfully ablates C6 glioma cells that express the gpt transgene at concentrations that have little or no effect on parental C6 cells. In subcutaneous and intracerebral models of rat C6 gliomas in athymic mice, the 6-TX/gpt gene therapy strategy was found to retard tumor growth. These findings demonstrate the potential therapeutic selectivity of the 6TX/gpt gene therapy strategy and suggest the value of further studies of this modality.