MODULATION OF 5-FLUOROURACIL RESISTANCE IN HUMAN COLON-TUMOR CELL-LINES BY AZIDOTHYMIDINE

5-fluorouracil (5-FU), an inhibitor of thymidylate synthase (EC 2.1.1. 45), is clinically used in the treatment of several solid tumors, incl uding colorectal, head and neck, gastric, and pancreatic cancer. The d rug effectively inhibits deoxynucleoside triphosphate de novo synthesi s. However, this inhibition can be circumvented by increased thymidine kinase (EC 2.7.1.21) activity. In the present study we examined the e ffects of 5-FU combined with azidothymidine (AZT), a competitive inhib itor of thymidine kinase in human colon tumor cells in vitro, includin g three 5-FU resistant cell lines. The cells were simultaneously incub ated with various concentrations of 5-FU (0.015 to 150 mu M) and AZT ( 20 to 300 mu M) for 6 days. 5-FU alone yielded an IC50 of 18 mu M in t he parental CCL 227 cell line and IC(50)s of 470 and 1100 mu M in the 5-FU resistant cell lines as determined by a MTT chemosensitivity assa y. Addition of 100 mu M AZT alone, a drug concentration that can be ac hieved in patients, had no effect on the growth of the cell lines exam ined. However, when added simultaneously with 5-FU, the IC(50)s of 5-F U synergistically decreased to 10 mu M in the sensitive and to 360 or 760 mu M in the resistant cell lines, respectively. Our results demons trate that the combination of 5-FU with AZT synergistically inhibited the growth of 5-FU resistant cells, suggesting the use of 5-FU in comb ination with AZT for the treatment of 5-FU sensitive as well as resist ant human colon tumors.