LACK OF DEPENDENCE OF 5-FLUORODEOXYURIDINE-MEDIATED RADIOSENSITIZATION ON CYTOTOXICITY

It has been proposed that fluoropyrimidine-mediated cytotoxicity and r adiosensitization are closely correlated. We have shown that HT29 huma n colon cancer cells transfected with the E. coli dUTPase gene are res istant to 5-fluorodeoxyuridine (FdUrd)-mediated cytotoxicity, presumab ly through more effective elimination of dUTP. We used these cells to assess the association between radiosensitization and cytotoxicity pro duced by FdUrd. The radiation sensitivities of the clones expressing e levated dUTPase activity (dutE clones) were similar to those of untran sfected HT29 cells or HT29 cells which had been transfected with only the expression vector for the E. coli gene (con clones). We found that FdUrd produced similar increases in radiation sensitivity regardless of dUTPase activity. Levels of dUTPase in the dutE clones remained ele vated during the entire period of FdUrd exposure, demonstrating that t he lack of difference between dutE and Con clones was not a reflection of down-regulation of dUTPase activity by FdUrd. Flow cytometry showe d that all clones progressed past the G(1)/S-phase boundary and into e arly S phase during FdUrd treatment. These data suggest that the mecha nisms of FdUrd-mediated cytotoxicity and radiosensitization are not cl osely linked. These findings, combined with our previous investigation s, are consistent with the hypothesis that radiosensitization occurs i n cells which progress past the G(1)/S-phase boundary in the presence of FdUrd. (C) 1995 by Radiation Research Society