INCREASED SENSITIVITY TO LONG-TERM 5-FLUOROURACIL EXPOSURE OF HUMAN COLON-CANCER HT-29 CELLS RESISTANT TO SHORT-TERM EXPOSURE

A 5-fluorouracil (5-FU)-resistant subline of human colon cancer HT-29 cells was developed by repeated 1-h exposure in vitro to 5-FU. This su bline (HT-29/5-FU/S) had 8-fold resistance to 5-FU in a 1-h exposure a ssay. However, it had rather increased sensitivity to 5-FU when assaye d after a continuous 96-h exposure to it, Significantly less 5-fluorou ridine-5'-triphosphate mas produced in the resistant cells, leading to a lower level of 5-FU incorporation into the cellular RNA, The reduce d activity of orotate phosphoribosyltransferase might explain these re sults, In contrast, the HT-29/5-FU/S cells were more sensitive to the inhibition of in situ thymidylate synthase (TS) by 5-FU than were the parent cells, The lower in situ TS activity may have made HT-29/5-FU/S cells more sensitive to TS inhibition by 5-FU as compared with the pa rent cells, The fact that HT-29/5-FU/S was more resistant to short-ter m 5-FU exposure but more sensitive to long-term exposure than the pare nt line confirmed the existence of different modes of action of 5-FU, depending on the exposure time.