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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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Sequential 19F MR spectra (4.23 T) obtained in vivo from a subcutaneous C26-B ((A) 0.39 cm3) or C26-10 ((B) 0.45 cm3) murine colon carcinoma in a Balb/C mouse following injection of a bolus i.p. dose of 5-FU (150 mg kg−1) at time t=0. Data acquisition was started simultaneously with the 5-FU injection, and sequential 8.5-min data blocks (FIDs) were stored. To improve the S/N for the presentation, each spectrum shown was obtained by adding two successive 8.5-min acquisitions (equivalent to 17 min of time averaging) before Fourier transformation. Peak labels: F=unmetabolized 5-FU (chemical shift defined as 0 ppm); C=the major catabolites FUPA (−16.5 ppm) and FBAL (−19.2 ppm); A=a composite signal at ca. 5 ppm representing the overlapping peaks from all fluoronucleotides in oxy (FUMP, FUDP, FUTP, FUDP-hexoses) and deoxy (FdUMP) forms.
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fig1: Sequential 19F MR spectra (4.23 T) obtained in vivo from a subcutaneous C26-B ((A) 0.39 cm3) or C26-10 ((B) 0.45 cm3) murine colon carcinoma in a Balb/C mouse following injection of a bolus i.p. dose of 5-FU (150 mg kg−1) at time t=0. Data acquisition was started simultaneously with the 5-FU injection, and sequential 8.5-min data blocks (FIDs) were stored. To improve the S/N for the presentation, each spectrum shown was obtained by adding two successive 8.5-min acquisitions (equivalent to 17 min of time averaging) before Fourier transformation. Peak labels: F=unmetabolized 5-FU (chemical shift defined as 0 ppm); C=the major catabolites FUPA (−16.5 ppm) and FBAL (−19.2 ppm); A=a composite signal at ca. 5 ppm representing the overlapping peaks from all fluoronucleotides in oxy (FUMP, FUDP, FUTP, FUDP-hexoses) and deoxy (FdUMP) forms.

Mentions: For the presentation in Figure 1Figure 1


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)

Sequential 19F MR spectra (4.23 T) obtained in vivo from a subcutaneous C26-B ((A) 0.39 cm3) or C26-10 ((B) 0.45 cm3) murine colon carcinoma in a Balb/C mouse following injection of a bolus i.p. dose of 5-FU (150 mg kg−1) at time t=0. Data acquisition was started simultaneously with the 5-FU injection, and sequential 8.5-min data blocks (FIDs) were stored. To improve the S/N for the presentation, each spectrum shown was obtained by adding two successive 8.5-min acquisitions (equivalent to 17 min of time averaging) before Fourier transformation. Peak labels: F=unmetabolized 5-FU (chemical shift defined as 0 ppm); C=the major catabolites FUPA (−16.5 ppm) and FBAL (−19.2 ppm); A=a composite signal at ca. 5 ppm representing the overlapping peaks from all fluoronucleotides in oxy (FUMP, FUDP, FUTP, FUDP-hexoses) and deoxy (FdUMP) forms.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Sequential 19F MR spectra (4.23 T) obtained in vivo from a subcutaneous C26-B ((A) 0.39 cm3) or C26-10 ((B) 0.45 cm3) murine colon carcinoma in a Balb/C mouse following injection of a bolus i.p. dose of 5-FU (150 mg kg−1) at time t=0. Data acquisition was started simultaneously with the 5-FU injection, and sequential 8.5-min data blocks (FIDs) were stored. To improve the S/N for the presentation, each spectrum shown was obtained by adding two successive 8.5-min acquisitions (equivalent to 17 min of time averaging) before Fourier transformation. Peak labels: F=unmetabolized 5-FU (chemical shift defined as 0 ppm); C=the major catabolites FUPA (−16.5 ppm) and FBAL (−19.2 ppm); A=a composite signal at ca. 5 ppm representing the overlapping peaks from all fluoronucleotides in oxy (FUMP, FUDP, FUTP, FUDP-hexoses) and deoxy (FdUMP) forms.
Mentions: For the presentation in Figure 1Figure 1

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