Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma.
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.
Kamm
Y J L
YJ
Department of Medical Oncology 550, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. y.kamm@onco.umcn.nl
Peters
G J
GJ
Hull
W E
WE
Punt
C J A
CJ
Heerschap
A
A
D000280:Administration, Inhalation; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002245:Carbon Dioxide / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010100:Oxygen / Q000008:administration & dosage; D012334:RNA, Neoplasm / Q000378:metabolism; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D012334:RNA, Neoplasm; D005468:Fluorodeoxyuridylate; D002245:Carbon Dioxide; C011700:carbogen; D013940:Thymidylate Synthase; D010100:Oxygen; D005472:Fluorouracil