Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma

Abstract

Following an i.p. dose of 150 mg kg À1 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 ¼ 11) and C26-10 (5-FUsensitive; n ¼ 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.

N-(4-iodophenyl)-N′-(2-chloroethyl)urea as a microtubule disrupter: in vitro and in vivo profiling of antitumoral activity on CT-26 murine colon carcinoma cell line cultured and grafted to mice

“…Tumour uptake of [ 125 I]ICEU reached a stable maximal value of 3.370.3% ID g À1 . To our knowledge, this level of drug accumulation in the tumour appears higher than that of 5-Fu accumulation, that is the current 'gold standard' drug for the first-line of colorectal cancer treatment, reported in the same CT-26 tumour-bearing mice model (Kamm et al, 2003). These data appeared to us of particular interest since they supported our previous findings demonstrating that 40 mmol kg À1 of ICEU administered i.p.…”

Monitoring fluoropyrimidine metabolism in solid tumors with in vivo 19F magnetic resonance spectroscopy

“…It was hypothesized that for this tumor type, FU uptake was not a rate-limiting process for growth inhibition, possibly due to the relatively small size and well-perfused condition of the tumors. In C26B and C26-10 tumors in BalbC mice, there was no effect of carbogen breathing on FU uptake or anabolite production; however, carbogen + FU significantly inhibited tumor growth in C26-10 tumors [90]. The reason for the prolonged growth delay in C26-10 remained unclear in this study.…”

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours

“…However, carbogen had no significant effect on 5FU uptake and metabolism in small RIF-1 tumours (0.8-1.6 g or 2.5-5% body-weight). These observations suggest the effects of carbogen on tumours may not be universal, and indeed different research groups using different tumour models have observed no change as well as both implied and real increases and decreases in tumour oxygenation, blood flow, pH and energy status [1,6,8,12,14,15,28,39]. We decided therefore to investigate the effects of carbogen on the pharmacokinetics of 5FU in two additional rodent tumour models, which have shown significant physiological responses to carbogen [29,35].…”