Escherichia coli thymidylate synthase expression protects human cells fromthe cytotoxic effects of 5-fluorodeoxyuridine more effectively than human thymidylate synthase overexpression

In th is study, we compared the relative abilities of human thymidylate syn thase (hTS) and Escherichia coli thymidylate synthase (eTS) expression to c onfer resistance to the cytotoxic effects of treatment with the TS inhibito r 5-fluorodeoxyuridine (FdUrd). C418-selected clones expressing either form of the protein were significantly more resistant than the lacZ-expressing clone, VALZ2, to FdUrd-induced cytoxicity. Although eTS-expressing clones e xpressed 2- to 3-fold more TS protein than hTS-overexpressing clones, the r epresentative eTS-expressing clone, VAEG8, and hTS-overexpressing clone, VA HGC, were equally sensitive to an FdUrd-induced loss of clonogenicity; in a ddition, a large fraction of either form of exogenously expressed TS appear ed to be inactive in the intact cell. The clones differed, however, in thei r responses to leucovorin (LV). Although LV significantly enhanced FdUrd-in duced TS inhibition, growth inhibition, and cytotoxicity in VAHGC cells, it had no effect on these parameters in VAEG8 cells. These results suggest th at eTS may more efficiently confer resistance to FdUrd plus LV when express ed for the purposes of a "host protection" strategy in vivo.