Journal article
Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance
Anti-cancer drugs, Vol.9(7), pp.625-634
08/1998
DOI: 10.1097/00001813-199808000-00008
PMID: 9773807
Abstract
Recent preclinal 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 (ICso) 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.
Details
- Title: Subtitle
- Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance
- Creators
- A Harstrick - Centre Antoine LacassagneA GonzalesN SchleucherU VanhoeferKun LuJ L FormentoG MilanoH WilkeS SeeberY Rustum
- Resource Type
- Journal article
- Publication Details
- Anti-cancer drugs, Vol.9(7), pp.625-634
- Publisher
- Lippincott-Raven Publishers
- DOI
- 10.1097/00001813-199808000-00008
- PMID
- 9773807
- ISSN
- 0959-4973
- eISSN
- 1473-5741
- Language
- English
- Date published
- 08/1998
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359667802771
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