TY - JOUR
T1 - 5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers
AU - Noordhuis, P.
AU - Holwerda, U.
AU - Van der Wilt, C. L.
AU - Van Groeningen, C. J.
AU - Smid, K.
AU - Meijer, S.
AU - Pinedo, H. M.
AU - Peters, G. J.
PY - 2004/7
Y1 - 2004/7
N2 - Background: The mechanism of action of 5-fluorouracil (5-FU) has been associated with inhibition of thymidylate synthase (TS) and incorporation of 5-FU into RNA and DNA, but limited data are available in human tumor tissue for the latter. We therefore measured incorporation in human tumor biopsy specimens after administration of a test dose of 5-FU alone or with leucovorin. Patients and methods: Patients received 5-FU (500 mg/m2) with or without high-dose leucovorin, low-dose leucovorin or 1-leucovorin, and biopsy specimens were taken after approximately 2, 24 or 48 h. Tissues were pulverized and extracted for nucleic acids. 5-FU incorporation was measured using gas chromatography/mass spectrometry after complete degradation to bases of isolated RNA and DNA. Results: Maximal incorporation into RNA (1.0 pmol/μg RNA) and DNA (127 fmol/μg DNA) of 59 and 46 biopsy specimens, respectively, was found at 24 h after 5-FU administration. Incorporation into RNA but not DNA was significantly correlated with intratumoral 5-FU levels. However, DNA incorporation was significantly correlated with the RNA incorporation. Primary tumor tissue, liver metastasis and normal mucosa did not show significant differences, while leucovorin had no effect. Neither for RNA (30 patients) nor DNA (24 patients) incorporation was a significant correlation with response to 5-FU therapy found. However, in the same group of patients, response was significantly correlated to TS inhibition (mean TS in responding and non-responding groups 45 and 231 pmol/h/mg protein, respectively; P = 0.001). Conclusions: 5-FU is incorporated at detectable levels into RNA and DNA of human tumor tissue, but no relation between the efficacy of 5-FU treatment and incorporation was found, in contrast to TS.
AB - Background: The mechanism of action of 5-fluorouracil (5-FU) has been associated with inhibition of thymidylate synthase (TS) and incorporation of 5-FU into RNA and DNA, but limited data are available in human tumor tissue for the latter. We therefore measured incorporation in human tumor biopsy specimens after administration of a test dose of 5-FU alone or with leucovorin. Patients and methods: Patients received 5-FU (500 mg/m2) with or without high-dose leucovorin, low-dose leucovorin or 1-leucovorin, and biopsy specimens were taken after approximately 2, 24 or 48 h. Tissues were pulverized and extracted for nucleic acids. 5-FU incorporation was measured using gas chromatography/mass spectrometry after complete degradation to bases of isolated RNA and DNA. Results: Maximal incorporation into RNA (1.0 pmol/μg RNA) and DNA (127 fmol/μg DNA) of 59 and 46 biopsy specimens, respectively, was found at 24 h after 5-FU administration. Incorporation into RNA but not DNA was significantly correlated with intratumoral 5-FU levels. However, DNA incorporation was significantly correlated with the RNA incorporation. Primary tumor tissue, liver metastasis and normal mucosa did not show significant differences, while leucovorin had no effect. Neither for RNA (30 patients) nor DNA (24 patients) incorporation was a significant correlation with response to 5-FU therapy found. However, in the same group of patients, response was significantly correlated to TS inhibition (mean TS in responding and non-responding groups 45 and 231 pmol/h/mg protein, respectively; P = 0.001). Conclusions: 5-FU is incorporated at detectable levels into RNA and DNA of human tumor tissue, but no relation between the efficacy of 5-FU treatment and incorporation was found, in contrast to TS.
KW - 5-Fluorouracil
KW - 5-FU incorporation into DNA
KW - 5-FU incorporation into RNA
KW - Human colorectal cancer
KW - Leucovorin
KW - Thymidylate synthase inhibition
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U2 - 10.1093/annonc/mdh264
DO - 10.1093/annonc/mdh264
M3 - Article
C2 - 15205195
AN - SCOPUS:4143083857
SN - 0923-7534
VL - 15
SP - 1025
EP - 1032
JO - Annals of Oncology
JF - Annals of Oncology
IS - 7
ER -