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 subline (HT-29/5-FU/S) had 8-fold resistance to 5-FU in a 1-h exposure assay. However, it had rather increased sensitivity to 5-FU when assayed after a continuous 96-h exposure to it. Significantly less 5-fluorouridine-5'-triphosphate was produced in the resistant cells, leading to a lower level of 5-FU incorporation into the cellular RNA. The reduced activity of orotate phosphoribosyltransferase might explain these results. 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 parent cells. The fact that HT-29/5-FU/S was more resistant to short-term 5-FU exposure but more sensitive to long-term exposure than the parent line confirmed the existence of different modes of action of 5-FU, depending on the exposure time.
Inaba
M
M
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Tanaka
T
T
Sawada
H
H
D003110:Colonic Neoplasms; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage*; D019073:HT29 Cells / Q000187:drug effects*; D006801:Humans; D013940:Thymidylate Synthase / Q000378:metabolism; D013997:Time Factors
D013940:Thymidylate Synthase; D005472:Fluorouracil