METABOLISM OF 5-FLUOROCYTOSINE TO 5-FLUOROURACIL IN HUMAN COLORECTAL TUMOR-CELLS TRANSDUCED WITH THE CYTOSINE DEAMINASE GENE - SIGNIFICANT ANTITUMOR EFFECTS WHEN ONLY A SMALL PERCENTAGE OF TUMOR-CELLS EXPRESS CYTOSINE DEAMINASE

The gene encoding cytosine deaminase (CD) has been expressed in the hu man colorectal carcinoma cell line WiDr. Metabolism studies confirm th at tumor cells expressing CD convert the very nontoxic prodrug 5-fluor ocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tum or xenografts composed of CD-expressing cells fan selectively generate tumor levels of >400 mu M 5FUra when the host mouse is dosed with non toxic levels of 5FCyt. The selective metabolic conversion of 5FCyt to 5FUra in CD-expressing tumor cells results in the inhibition of thymid ylate synthase and incorporation of 5FUra into RNA. 5FUra is also Libe rated into the surrounding environment when CD-expressing tumor cells are treated with 5FCyt. The liberated 5FUra is able to kill neighborin g, non-CD-expressing tumor cells in vitro and in vivo. Most importantl y, when only 2% of the tumor mass contains CD-expressing cells (98% no n-CD-expressing cells), significant regressions in all tumors are obse rved when the host mouse is dosed with nontoxic levels of 5FCyt.