Annals of Oncology 15:1025-1032, 2004
© 2004 European Society for Medical Oncology
5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers
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 l-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.
Departments of 1 Medical Oncology, 2 Clinical Chemistry; 3 Surgical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Present address: Comprehensive Cancer Center Amsterdam (IKA), Amsterdam, The Netherlands.
*Correspondence to: Dr G. J. Peters, Department of Medical Oncology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands. Tel: +31-20-4442633; Fax: +31-20-4443844; Email: gj.peters{at}vumc.nl
Key words: 5-fluorouracil, 5-FU incorporation into DNA, 5-FU incorporation into RNA, human colorectal cancer, leucovorin, thymidylate synthase inhibition
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. R. Brody, T. Hucl, C. L. Costantino, J. R. Eshleman, E. Gallmeier, H. Zhu, M. S. van der Heijden, J. M. Winter, A. K. Wikiewicz, C. J. Yeo, et al. Limits to Thymidylate Synthase and TP53 Genes as Predictive Determinants for Fluoropyrimidine Sensitivity and Further Evidence for RNA-Based Toxicity as a Major Influence Cancer Res., February 1, 2009; 69(3): 984 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. An, P. Robins, T. Lindahl, and D. E. Barnes 5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity Cancer Res., February 1, 2007; 67(3): 940 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fischer, S. Muller-Weeks, and S. J. Caradonna Fluorodeoxyuridine Modulates Cellular Expression of the DNA Base Excision Repair Enzyme Uracil-DNA Glycosylase. Cancer Res., September 1, 2006; 66(17): 8829 - 8837. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Smorenburg, G. J. Peters, C. J. van Groeningen, P. Noordhuis, K. Smid, A. M. G. H. van Riel, W. Dercksen, H. M. Pinedo, and G. Giaccone Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase Ann. Onc., January 1, 2006; 17(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|