1. Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma.
- Author
-
Kamm YJ, Peters GJ, Hull WE, Punt CJ, and Heerschap A
- Subjects
- Administration, Inhalation, Animals, Carbon Dioxide administration & dosage, Female, Fluorodeoxyuridylate metabolism, Magnetic Resonance Spectroscopy methods, Mice, Mice, Inbred BALB C, Neoplasm Transplantation, Oxygen administration & dosage, RNA, Neoplasm metabolism, Survival Rate, Thymidylate Synthase metabolism, Antimetabolites, Antineoplastic pharmacokinetics, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Fluorouracil pharmacokinetics
- Abstract
Following an i.p. dose of 150 mg x kg(-1) 5-fluorouracil (5-FU), drug uptake and metabolism over a 2-h period were studied by in vivo (19)F magnetic resonance spectroscopy (MRS) for the murine colon carcinoma lines C26-B (5-FU-insensitive; n=11) and C26-10 (5-FU-sensitive; n=15) implanted s.c. in Balb/C mice. Time courses for tumour growth, intracellular levels of FdUMP, thymidylate synthase (TS) activity, and 5-FU in RNA were also determined, and the effects of a 9.5-min period of carbogen breathing, starting 1 min before drug administration, on MRS-detected 5-FU metabolism and tumour growth curves were examined. Both tumour variants generated MRS-detectable 5-FU nucleotides and showed similar initial growth inhibition after treatment. However, the growth rate of C26-B tumours returned to normal, while the sensitive C26-10 tumours, which produced larger fluoronucleotide pools, still showed moderate growth inhibition. Carbogen breathing did not significantly influence 5-FU uptake or fluoronucleotide production but did significantly enhance growth inhibition in C26-10 tumours. While both tumour variants exhibited incorporation of 5-FU into RNA and inhibition of TS via FdUMP, clearance of 5-FU from RNA and recovery of TS activity were greater for the insensitive C26-B line, indicating that these processes, in addition to 5-FU uptake and metabolism, may be important determinants of drug sensitivity and treatment response.
- Published
- 2003
- Full Text
- View/download PDF