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

Kamm YJ, Peters GJ, Hull WE, Punt CJ, Heerschap A - Br. J. Cancer (2003)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology 550, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. y.kamm@onco.umcn.nl

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.

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Normalised growth curves (relative tumour volume: mean±s.d.) for s.c. implanted colon carcinoma C26-B and C26-10 in Balb/C mice after i.p. bolus treatment with 150 mg kg−1 5-FU alone (C26-B, n=9; C26-10, n=11) or in combination with 9.5-min carbogen breathing (C26-B, n=11; C26-10, n=10). Two-way ANOVA indicates that differences between tumour variants are highly significant with or without carbogen: group 1 vs 3, P=0.02; group 2 vs 4, P=0.003. A significant effect of carbogen was observed only for the more slowly growing, 5-FU-sensitive C26-10 tumours: group 1 vs 2, P=0.35; group 3 vs 4, P=0.03.
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fig2: Normalised growth curves (relative tumour volume: mean±s.d.) for s.c. implanted colon carcinoma C26-B and C26-10 in Balb/C mice after i.p. bolus treatment with 150 mg kg−1 5-FU alone (C26-B, n=9; C26-10, n=11) or in combination with 9.5-min carbogen breathing (C26-B, n=11; C26-10, n=10). Two-way ANOVA indicates that differences between tumour variants are highly significant with or without carbogen: group 1 vs 3, P=0.02; group 2 vs 4, P=0.003. A significant effect of carbogen was observed only for the more slowly growing, 5-FU-sensitive C26-10 tumours: group 1 vs 2, P=0.35; group 3 vs 4, P=0.03.

Mentions: Normalised growth curves for s.c. C26-B and C26-10 tumours in Balb/C mice following i.p. bolus 5-FU treatment are shown in Figure 2Figure 2


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

Kamm YJ, Peters GJ, Hull WE, Punt CJ, Heerschap A - Br. J. Cancer (2003)

Normalised growth curves (relative tumour volume: mean±s.d.) for s.c. implanted colon carcinoma C26-B and C26-10 in Balb/C mice after i.p. bolus treatment with 150 mg kg−1 5-FU alone (C26-B, n=9; C26-10, n=11) or in combination with 9.5-min carbogen breathing (C26-B, n=11; C26-10, n=10). Two-way ANOVA indicates that differences between tumour variants are highly significant with or without carbogen: group 1 vs 3, P=0.02; group 2 vs 4, P=0.003. A significant effect of carbogen was observed only for the more slowly growing, 5-FU-sensitive C26-10 tumours: group 1 vs 2, P=0.35; group 3 vs 4, P=0.03.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376920&req=5

fig2: Normalised growth curves (relative tumour volume: mean±s.d.) for s.c. implanted colon carcinoma C26-B and C26-10 in Balb/C mice after i.p. bolus treatment with 150 mg kg−1 5-FU alone (C26-B, n=9; C26-10, n=11) or in combination with 9.5-min carbogen breathing (C26-B, n=11; C26-10, n=10). Two-way ANOVA indicates that differences between tumour variants are highly significant with or without carbogen: group 1 vs 3, P=0.02; group 2 vs 4, P=0.003. A significant effect of carbogen was observed only for the more slowly growing, 5-FU-sensitive C26-10 tumours: group 1 vs 2, P=0.35; group 3 vs 4, P=0.03.
Mentions: Normalised growth curves for s.c. C26-B and C26-10 tumours in Balb/C mice following i.p. bolus 5-FU treatment are shown in Figure 2Figure 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology 550, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. y.kamm@onco.umcn.nl

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.

Show MeSH
Related in: MedlinePlus