Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance.
Recent preclinical and clinical data indicate that the main mechanisms of 5-fluorouracil (5-FU) cytotoxicity depend on the mode of administration. To gather further insight into the major causes of acquired 5-FU resistance, drug-sensitive human gastric (M2), colon (HT29) and breast (MCF7) cancer cell lines were repeatedly exposed to a fixed concentration of 5-FU given either for 1 or 24 h. Although equieffective doses (IC50) of 5-FU were used, resistance to a 1 h exposure of 5-FU developed faster in all models than to a 24 h exposure. Cell lines with acquired resistance to a 1 h application of 5-FU were only partly cross-resistant to a 24 h exposure, whereas lines with resistance to protracted application of 5-FU displayed significant cross-resistance to the 1 h schedule. Resistance to methotrexate was only seen in cell lines with acquired resistance to 24 h of 5-FU. All 5-FU-resistant cell lines showed reduced incorporation of 5-FU into cellular RNA. Furthermore, elevations of thymidylate synthase were seen in all cell lines with resistance to 24 h of 5-FU but also in one cell line with resistance to a bolus schedule. No alterations in folylpolyglutamate synthase developed in the resistant cell lines. These data support the concept that the main mechanisms of 5-FU cytotoxicity depend on the mode of application. Incorporation of fluorouridine triphosphate into RNA appears to be the most important mechanism of action for 5-FU bolus schedules, whereas inhibition of thymidylate synthase becomes more important as the infusion time is prolonged. These data could have implications on the interaction of 5-FU given at different schedules with various other cytostatic agents.
Harstrick
A
A
Department of Internal Medicine, West German Cancer Center, Essen.
Gonzales
A
A
Schleucher
N
N
Vanhoefer
U
U
Lu
K
K
Formento
J L
JL
Milano
G
G
Wilke
H
H
Seeber
S
S
Rustum
Y
Y
D000230:Adenocarcinoma / Q000188:drug therapy*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D020128:Inhibitory Concentration 50; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil