Skip to main content
Log in

Enhanced cytotoxicity of 5-FU by bFGF through up-regulation of uridine phosphorylase 1

  • Published:
Molecules and Cells

Abstract

Anti cancer agent 5-FU (Fluoro Uracil) is a prodrug that can be metabolized and then activated to interfere with RNA and DNA homeostasis. However, the majority of administered 5-FU is known to be catabolized in vivo in the liver where Dihydropyrimidine dehydrogenase (DPD) is abundantly expressed to degrade 5-FU. The biological factors that correlate with the response to 5-FU-based chemotherapy have been proposed to include uridine phosphorylase (UPP), thymidine phosphorylase (TPP), p53 and microsatellite instability. Among these, the expression of UPP is known to be controlled by cytokines such as TNF-α, IL1 and IFN-γ. Our preliminary study using a DNA microarray technique showed that basic fibroblast growth factor (bFGF) markedly induced the expression of UPP1 at the transcription level. In the present study, we investigated whether bFGF could modulate the expression of UPP1 in osteo-lineage cells and examined the sensitivity of these cells to 5-FU mediated apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Al Safarjalani, O.N., Zhou, X.J., Rais, R.H., Shi, J., Schinazi, R.F., Naguib, F.N., and El Kouni, M.H. (2005). 5-(Phenylthio) acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens. Cancer Chemother. Pharmacol. 55, 541–551.

    Article  PubMed  Google Scholar 

  • Baynes, J.W., and Dominiczak, M.H. (2005). Medical Biochemistry (Elsevier Mosby), pp.417–423.

  • Cao, D., and Pizzorno, G. (2004). Uridine phosophorylase: an important enzyme in pyrimidine metabolism and fluoropyrimidine activation. Drugs Today (Barc.) 40, 431–443.

    Article  CAS  Google Scholar 

  • Diasio, R.B., and Harris, B.E. (1989). Clinical pharmacology of 5-fluorouracil. Clin. Pharmacokinet. 16, 215–237.

    Article  PubMed  CAS  Google Scholar 

  • Douillard, J.Y., Cunningham, D., Roth, A.D., Navarro, M., James, R.D., Karasek, P., Jandik, P., Iveson, T., Carmichael, J., Alakl, M., et al. (2000). Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355, 1041–1047.

    Article  PubMed  CAS  Google Scholar 

  • el Kouni, M.H., Naguib, F.N., Park, K.S., Cha, S., Darnowski, J.W., and Soong, S.J. (1990). Circadian rhythm of hepatic uridine phosphorylase activity and plasma concentration of uridine in mice. Biochem. Pharmacol. 40, 2479–2485.

    Article  PubMed  Google Scholar 

  • Geng, Y., Gheuens, E., and de Bruijn, E.A. (1991). Activation and cytotoxicity of 5′-deoxy-5-fluorouridine in c-H-ras transformed NIH 3T3 cells. Biochem. Pharmacol. 41, 301–303.

    Article  PubMed  CAS  Google Scholar 

  • Giacchetti, S., Perpoint, B., Zidani, R., Le, B.N., Faggiuolo, R., Focan, C., Chollet, P., Llory, J.F., Letourneau, Y., Coudert, B., et al. (2000). Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 18, 136–147.

    PubMed  CAS  Google Scholar 

  • Greco, F.A., Figlin, R., York, M., Einhorn, L., Schilsky, R., Marshall, E.M., Buys, S.S., Froimtchuk, M.J., Schuller, J., Schuchter, L., et al. (1996). Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J. Clin. Oncol. 14, 2674–2681.

    PubMed  CAS  Google Scholar 

  • Johnston, P.G., and Kaye, S. (2001). Capecitabine: a novel agent for the treatment of solid tumors. Anticancer Drugs 12, 639–646.

    Article  PubMed  CAS  Google Scholar 

  • Kim, S., Park, D.H., and Shim, J. (2008). Thymidylate synthase and dihydropyrimidine dehydrogenase levels are associated with response to 5-fluorouracil in Caenorhabditis elegans. Mol. Cells 16, 344–349.

    Google Scholar 

  • Lee, S.J., Lee, H.K., Cho, S.Y., Choi, J.K., Shin, H.K., Kwak, E.J., Cho, M.R., Kim, H.R., Kim, S.R., Kim, Y.M., et al. (2008). Identification of osteogenic purmorphamine deriva-tives. Mol. Cells 26, 380–386.

    PubMed  CAS  Google Scholar 

  • Longley, D.B., Harkin, D.P., and Johnston, P.G. (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338.

    Article  PubMed  CAS  Google Scholar 

  • Moyer, J.D., Oliver, J.T., and Handschumacher, R.E. (1981). Salvage of circulating pyrimidine nucleosides in the rat. Cancer Res. 41, 3010–3017.

    PubMed  CAS  Google Scholar 

  • Schwartz, E.L., Wan, E., Wang, F.S., and Baptiste, N. (1998). Regulation of expression of thymidine phosphorylase/plateletderived endothelial cell growth factor in human colon carcinoma cells. Cancer Res. 58, 1551–1557.

    PubMed  CAS  Google Scholar 

  • Seymour, M.T., Slevin, M.L., Kerr, D.J., Cunningham, D., James, R.D., Ledermann, J.A., Perren, T.J., McAdam, W.A., Harper, P.G., Neoptolemos, J.P., et al. (1996). Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council. J. Clin. Oncol. 14, 2280–2288.

    PubMed  CAS  Google Scholar 

  • Voboril, R., Hochwald, S.N., Li, J., Brank, A., Weberova, J., Wessels, F., Moldawer, L.L., Camp, E.R., and MacKay, S.L. (2004). Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J. Surg. Res. 120, 178–188.

    Article  PubMed  CAS  Google Scholar 

  • Wan, L., Cao, D., Zeng, J., Yan, R., and Pizzorno, G. (2006). Modulation of uridine phosphorylase gene expression by tumor necrosis factor-alpha enhances the antiproliferative activity of the capecitabine intermediate 5′-deoxy-5-fluorouridine in breast cancer cells. Mol. Pharmacol. 69, 1389–1395.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joong-Kook Choi.

About this article

Cite this article

Im, YS., Shin, H.K., Kim, HR. et al. Enhanced cytotoxicity of 5-FU by bFGF through up-regulation of uridine phosphorylase 1. Mol Cells 28, 119–124 (2009). https://doi.org/10.1007/s10059-009-0116-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-009-0116-x

Keywords

Navigation