Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine

Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phospho ribosyltransferase (UPRT) gene, which is absent from mammalian cells, direc tly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate, We evaluated whether the coexpression of CD and UPRT genes could generate a sy nergistic antitumor effect on experimental brain tumors, In vitro study sho wed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 tim es more sensitive to 5-FC than parent cells, indicating that the acquisitio n of CD and UPRT further increased the 5-FC sensitivity of 9L cells compare d with cells transduced with CD alone. In a rat brain tumor model, decrease d amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT, CD and UPRT coexpression followed by 5-FC ad ministration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival, Th ese results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitu mor effect of 5-FC/CD gene therapy, Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.