The fluoropyrimidine 5-fluorouracil (5-FU) is an antimetabolite drug that is widely used for the treatment of cancer, particularly for colorectal cancer.
5-FU exerts its anticancer effects through inhibition of thymidylate synthase (TS) and incorporation of its metabolites into RNA and DNA.
Modulation strategies, such as co-treatment with leucovorin and methotrexate, have been developed to increase the anticancer activity of 5-FU.
Molecular biomarkers that predict tumour sensitivity to 5-FU have been identified, including mRNA and protein expression levels of TS.
DNA microarray analysis of 5-FU-responsive genes will greatly facilitate the identification of new biomarkers, novel therapeutic targets and the development of rational drug combinations.
5-Fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.
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Rutman, R. J., Cantarow, A. & Paschkis, K. E. Studies on 2-acetylaminofluorene carcinogenesis: III. The utilization of uracil-2-C14 by pre–neoplastic rat liver. Cancer Res. 14, 119 (1954).
IMPACT. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 345, 939–944 (1995).
Johnston, P. G. & Kaye, S. Capecitabine: a novel agent for the treatment of solid tumors. Anticancer Drugs 12, 639–646 (2001).
Giacchetti, S. et al. 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 (2000).
Douillard, J. Y. et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355, 1041–1047 (2000).
Wohlhueter, R. M., McIvor, R. S. & Plagemann, P. G. Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells. J. Cell Physiol. 104, 309–319 (1980).
Diasio, R. B. & Harris, B. E. Clinical pharmacology of 5-fluorouracil. Clin. Pharmacokinet. 16, 215–237 (1989).
Sommer, H. & Santi, D. V. Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2′-deoxyuridylate and methylenetetrahydrofolate. Biochem. Biophys. Res. Commun. 57, 689–695 (1974).
Santi, D. V., McHenry, C. S. & Sommer, H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13, 471–481 (1974).
Jackson, R. C. & Grindley, G. B. The Biochemical Basis for Methotrexate Cytotoxicity (eds Sirotnak, F. M., Burchall, J. J., Ensminger, W. D. & Montgomery, J. A.) 289–315 (Academic, New York, 1984).
Houghton, J. A., Tillman, D. M. & Harwood, F. G. Ratio of 2′-deoxyadenosine-5′-triphosphate/thymidine-5′-triphosphate influences the commitment of human colon carcinoma cells to thymineless death. Clin. Cancer Res. 1, 723–730 (1995).
Yoshioka, A. et al. Deoxyribonucleoside triphosphate imbalance. 5-Fluorodeoxyuridine-induced DNA double strand breaks in mouse FM3A cells and the mechanism of cell death. J. Biol. Chem. 262, 8235–8241 (1987).
Aherne, G. W., Hardcastle, A., Raynaud, F. & Jackman, A. L. Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells. Biochem. Pharmacol. 51, 1293–1301 (1996).
Mitrovski, B., Pressacco, J., Mandelbaum, S. & Erlichman, C. Biochemical effects of folate-based inhibitors of thymidylate synthase in MGH-U1 cells. Cancer Chemother. Pharmacol. 35, 109–114 (1994).
Lindahl, T. An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc. Natl Acad. Sci. USA 71, 3649–3653 (1974).
Webley, S. D., Hardcastle, A., Ladner, R. D., Jackman, A. L. & Aherne, G. W. Deoxyuridine triphosphatase (dUTPase) expression and sensitivity to the thymidylate synthase (TS) inhibitor ZD9331. Br. J. Cancer 83, 792–799 (2000).
Ladner, R. D. The role of dUTPase and uracil-DNA repair in cancer chemotherapy. Curr. Protein Pept. Sci. 2, 361–370 (2001).
Grem, J. L. & Fischer, P. H. Enhancement of 5-fluorouracil's anticancer activity by dipyridamole. Pharmacol. Ther. 40, 349–371 (1989).
Kufe, D. W. & Major, P. P. 5-Fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J. Biol. Chem. 256, 9802–9805 (1981).
Glazer, R. I. & Lloyd, L. S. Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. Mol. Pharmacol. 21, 468–473 (1982).
Kanamaru, R., Kakuta, H., Sato, T., Ishioka, C. & Wakui, A. The inhibitory effects of 5-fluorouracil on the metabolism of preribosomal and ribosomal RNA in L-1210 cells in vitro. Cancer Chemother. Pharmacol. 17, 43–46 (1986).
Ghoshal, K. & Jacob, S. T. Specific inhibition of pre-ribosomal RNA processing in extracts from the lymphosarcoma cells treated with 5-fluorouracil. Cancer Res. 54, 632–636 (1994).
Santi, D. V. & Hardy, L. W. Catalytic mechanism and inhibition of tRNA (uracil-5-)methyltransferase: evidence for covalent catalysis. Biochemistry 26, 8599–8606 (1987).
Randerath, K., Tseng, W. C., Harris, J. S. & Lu, L. J. Specific effects of 5-fluoropyrimidines and 5-azapyrimidines on modification of the 5 position of pyrimidines, in particular the synthesis of 5-methyluracil and 5-methylcytosine in nucleic acids. Recent Results Cancer Res. 84, 283–297 (1983).
Patton, J. R. Ribonucleoprotein particle assembly and modification of U2 small nuclear RNA containing 5-fluorouridine. Biochemistry 32, 8939–8944 (1993).
Doong, S. L. & Dolnick, B. J. 5-Fluorouracil substitution alters pre-mRNA splicing in vitro. J. Biol. Chem. 263, 4467–4473 (1988).
Samuelsson, T. Interactions of transfer RNA pseudouridine synthases with RNAs substituted with fluorouracil. Nucleic Acids Res. 19, 6139–6144 (1991).
Carrico, C. K. & Glazer, R. I. Effect of 5-fluorouracil on the synthesis and translation of polyadenylic acid-containing RNA from regenerating rat liver. Cancer Res. 39, 3694–3701 (1979).
Matherly, L. H., Czajkowski, C. A., Muench, S. P. & Psiakis, J. T. Role for cytosolic folate-binding proteins in the compartmentation of endogenous tetrahydrofolates and the 5-formyl tetrahydrofolate-mediated enhancement of 5-fluoro-2′-deoxyuridine antitumor activity in vitro. Cancer Res. 50, 3262–3269 (1990).
Park, J. G. et al. Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines. J. Natl Cancer Inst. 80, 1560–1564 (1988). In vitro studies such as this one were the basis for the clinical evaluation of 5-FU/leucovorin combination therapy.
Nadal, J. C., Van Groeningen, C. J., Pinedo, H. M. & Peters, G. J. In vivo potentiation of 5-fluorouracil by leucovorin in murine colon carcinoma. Biomed. Pharmacother. 42, 387–393 (1988).
Wright, J. E. et al. Selective expansion of 5, 0-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo. Cancer Res. 49, 2592–2596 (1989).
Dolnick, B. J. & Cheng, Y. C. Human thymidylate synthetase. II. Derivatives of pteroylmono- and -polyglutamates as substrates and inhibitors. J. Biol. Chem. 253, 3563–3567 (1978).
Radparvar, S., Houghton, P. J. & Houghton, J. A. Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft. Biochem. Pharmacol. 38, 335–342 (1989).
Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J. Clin. Oncol. 10, 896–903 (1992). This large meta-analysis confirmed that combining 5-FU with leucovorin significantly increased tumour response rates in advanced colorectal cancer.
Adjei, A. A. A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer. Br. J. Clin. Pharmacol. 48, 265–277 (1999).
Douillard, J. Y. et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J. Clin. Oncol. 20, 3605–3616 (2002).
Porter, D. J., Chestnut, W. G., Merrill, B. M. & Spector, T. Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J. Biol. Chem. 267, 5236–5242 (1992).
Takechi, T. et al. Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother. Pharmacol. 39, 205–211 (1997).
Spector, T., Cao, S., Rustum, Y. M., Harrington, J. A. & Porter, D. J. Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil. Cancer Res. 55, 1239–1241 (1995).
Miwa, M. et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur. J. Cancer 34, 1274–1281 (1998).
Cao, D., Russell, R. L., Zhang, D., Leffert, J. J. & Pizzorno, G. Uridine phosphorylase (−/−) murine embryonic stem cells clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in the activation of fluoropyrimidines. Cancer Res. 62, 2313–2317 (2002).
Schuller, J. et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother. Pharmacol. 45, 291–297 (2000).
Hoff, P. M. et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J. Clin. Oncol. 19, 2282–2292 (2001).
Gorlick, R. & Bertino, J. R. Clinical Pharmacology and Resistance to Dihydrofolate Reductase Inhibitors (ed. Jackman, A. L.) 37–57 (Humana Press, Totowa, New Jersey, 1999).
Benz, C., Tillis, T., Tattelman, E. & Cadman, E. Optimal schedule of methotrexate and 5-fluorouracil in human breast cancer. Cancer Res. 42, 2081–2086 (1982).
Bertino, J. R., Mini, E. & Fernandes, D. J. Sequential methotrexate and 5-fluorouracil: mechanisms of synergy. Semin. Oncol. 10, 2–5 (1983).
McSheehy, P. M., Prior, M. J. & Griffiths, J. R. Enhanced 5-fluorouracil cytotoxicity and increased 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo. Br. J. Cancer 65, 369–375 (1992).
Sawyer, R. C., Stolfi, R. L., Martin, D. S. & Balis, M. E. Inhibition by methotrexate of the stable incorporation of 5-fluorouracil into murine bone marrow DNA. Biochem. Pharmacol. 38, 2305–2311 (1989).
Cadman, E., Heimer, R. & Benz, C. The influence of methotrexate pretreatment on 5-fluorouracil metabolism in L1210 cells. J. Biol. Chem. 256, 1695–1704 (1981). This in vitro study showed that pre-treatment with methotrexate synergistically increased cell death in response to 5-FU.
Leyland-Jones, B. & O'Dwyer, P. J. Biochemical modulation: application of laboratory models to the clinic. Cancer Treat. Rep. 70, 219–229 (1986).
Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project. J. Clin. Oncol. 12, 960–969 (1994). This meta-analysis indicated that combining 5-FU with methotrexate increased response rates in metastatic colorectal cancer.
Houghton, J. A., Morton, C. L., Adkins, D. A. & Rahman, A. Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-alpha 2a in colon carcinoma cells. Cancer Res. 53, 4243–4250 (1993).
Eda, H. et al. Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5′-deoxy-5-fluorouridine. Jpn. J. Cancer Res. 84, 341–347 (1993).
Eda, H. et al. Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine. Cancer Chemother. Pharmacol. 32, 333–338 (1993).
Chu, E., Koeller, D. M., Johnston, P. G., Zinn, S. & Allegra, C. J. Regulation of thymidylate synthase in human colon cancer cells treated with 5-fluorouracil and interferon-gamma. Mol. Pharmacol. 43, 527–533 (1993).
Wadler, S., Lembersky, B., Atkins, M., Kirkwood, J. & Petrelli, N. Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J. Clin. Oncol. 9, 1806–1810 (1991).
Grem, J. L. et al. Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. J. Clin. Oncol. 11, 1737–1745 (1993).
Wolmark, N. et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J. Natl Cancer Inst. 90, 1810–1816 (1998). This study showed that adding interferon-α to adjuvant 5-FU/leucovorin chemotherapy did not significantly increase disease-free or overall survival of colorectal cancer patients.
Seymour, M. T. et al. 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 (1996).
Greco, F. A. et al. 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 (1996).
Johnston, P. G., Drake, J. C., Trepel, J. & Allegra, C. J. Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res. 52, 4306–4312 (1992).
Copur, S., Aiba, K., Drake, J. C., Allegra, C. J. & Chu, E. Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil. Biochem. Pharmacol. 49, 1419–1426 (1995).
Lenz, H. J. et al. p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival. Clin. Cancer Res. 4, 1243–1250 (1998).
Johnston, P. G. et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55, 1407–1412 (1995). This study showed that TS mRNA expression can be used as a surrogate for TS protein expression in clinical studies. In addition, both TS mRNA and protein expression predicted response of colorectal and gastric tumours to 5-FU.
Edler, D. et al. Immunohistochemical determination of thymidylate synthase in colorectal cancer: methodological studies. Eur. J. Cancer 33, 2278–2281 (1997).
Marsh, S. & McLeod, H. L. Thymidylate synthase pharmacogenomics in colorectal cancer. Clin. Colorectal Cancer 1, 175–178 (2001).
Horie, N., Aiba, H., Oguro, K., Hojo, H. & Takeishi, K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 20, 191–197 (1995).
Marsh, S., McKay, J. A., Cassidy, J. & McLeod, H. L. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int. J. Oncol. 19, 383–386 (2001).
Pullarkat, S. T. et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 1, 65–70 (2001). This study showed that polymorphisms in the TS promoter region affected TS expression levels in vivo and were predictive of tumour response to 5-FU in patients.
Kawakami, K., Omura, K., Kanehira, E. & Watanabe, Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 19, 3249–3252 (1999).
Swain, S. M. et al. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J. Clin. Oncol. 7, 890–899 (1989).
Chu, E. et al. Identification of a thymidylate synthase ribonucleoprotein complex in human colon cancer cells. Mol. Cell. Biol. 14, 207–213 (1994).
Evrard, A., Cuq, P., Ciccolini, J., Vian, L. & Cano, J. P. Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human colorectal cancer cells transfected with thymidine phosphorylase. Br. J. Cancer 80, 1726–1733 (1999).
Metzger, R. et al. High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil. Clin. Cancer Res. 4, 2371–2376 (1998).
Takebayashi, Y. et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J. Natl Cancer Inst. 88, 1110–1117 (1996).
Johnson, M. R. et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin. Cancer Res. 5, 2006–2011 (1999).
Johnson, M. R., Wang, K. & Diasio, R. B. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin. Cancer Res. 8, 768–774 (2002).
Takebe, N. et al. Retroviral transduction of human dihydropyrimidine dehydrogenase cDNA confers resistance to 5-fluorouracil in murine hematopoietic progenitor cells and human CD34+-enriched peripheral blood progenitor cells. Cancer Gene Ther. 8, 966–973 (2001).
Salonga, D. et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin. Cancer Res. 6, 1322–1327 (2000). Shows that analysis of three predictive markers (TS, TP and DPD) markedly enhanced the ability to predict tumour response to 5-FU-based chemotherapy compared with using a single biomarker.
Lane, D. P. Cancer. p53, guardian of the genome. Nature 358, 15–16 (1992).
Dotto, G. P. p21(WAF1/Cip1): more than a break to the cell cycle? Biochim. Biophys. Acta 1471, M43–M56 (2000).
Zhan, Q., Chen, I. T., Antinore, M. J. & Fornace, A. J., Jr. Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. Mol. Cell. Biol. 18, 2768–2778 (1998).
Miyashita, T. et al. Tumor suppressor p53 is a regulator of Bcl-2 and Bax gene expression in vitro and in vivo. Oncogene 9, 1799–1805 (1994).
Petak, I., Tillman, D. M. & Houghton, J. A. p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin. Cancer Res. 6, 4432–4441 (2000).
Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).
Longley, D. B. et al. The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. Cancer Res. 62, 2644–2649 (2002).
Zhang, L., Yu, J., Park, B. H., Kinzler, K. W. & Vogelstein, B. Role of BAX in the apoptotic response to anticancer agents. Science 290, 989–992 (2000).
Liang, J. T. et al. p53 overexpression predicts poor chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV colorectal cancers after palliative bowel resection. Int. J. Cancer 97, 451–457 (2002).
Elsaleh, H. et al. p53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin. Cancer Res. 7, 1343–1349 (2001).
Ahnen, D. J. et al. Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res. 58, 1149–1158 (1998). This clinical study found that patients with stage III colorectal cancer whose tumours overexpressed p53 did not benefit from adjuvant 5-FU-based chemotherapy, indicating that tumours with mutant TP53 are less responsive to 5-FU.
Paradiso, A. et al. Thymidylate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br. J. Cancer 82, 560–567 (2000).
Sjogren, S. et al. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J. Natl Cancer Inst. 88, 173–182 (1996).
Liu, B. et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nature Med. 2, 169–174 (1996).
Claij, N. & te Riele, H. Microsatellite instability in human cancer: a prognostic marker for chemotherapy? Exp. Cell Res. 246, 1–10 (1999).
Jacob, S. & Praz, F. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 84, 27–47 (2002).
Meyers, M., Wagner, M. W., Hwang, H. S., Kinsella, T. J. & Boothman, D. A. Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res. 61, 5193–5201 (2001).
Zembutsu, H. et al. Genome-wide cDNA microarray screening to correlate gene expression profiles with sensitivity of 85 human cancer xenografts to anticancer drugs. Cancer Res. 62, 518–527 (2002). One of the first studies to use DNA microarray profiling to identify subsets of genes that have expression levels that correlate with drug sensitivity.
Scherf, U. et al. A gene expression database for the molecular pharmacology of cancer. Nature Genet. 24, 236–244 (2000).
Kihara, C. et al. Prediction of sensitivity of esophageal tumors to adjuvant chemotherapy by cDNA microarray analysis of gene-expression profiles. Cancer Res. 61, 6474–6479 (2001).
Maxwell, P. J. et al. Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling. Cancer Res. (in the press).
Nagata, S. Fas ligand-induced apoptosis. Annu. Rev. Genet. 33, 29–55 (1999).
Houghton, J. A., Harwood, F. G. & Tillman, D. M. Thymineless death in colon carcinoma cells is mediated via fas signaling. Proc. Natl Acad. Sci. USA 94, 8144–8149 (1997).
Houghton, J. A., Harwood, F. G., Gibson, A. A. & Tillman, D. M. The Fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin. Cancer Res. 3, 2205–2209 (1997).
Wang, W., Marsh, S., Cassidy, J. & McLeod, H. L. Pharmacogenomic dissection of resistance to thymidylate synthase inhibitors. Cancer Res. 61, 5505–5510 (2001).
Raymond, E. Oxaliplatin: mechanism of action and antineoplastic activity. Semin. Oncol. 25, 4–12 (1998).
Voigt, W. et al. Topoisomerase-I inhibitor SN-38 can induce DNA damage and chromosomal aberrations independent from DNA synthesis. Anticancer Res. 18, 3499–3505 (1998).
Cunningham, D. et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352, 1413–1418 (1998).
Saltz, L. B. et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N. Engl. J. Med. 343, 905–914 (2000).
This work was supported by Cancer Research UK; the Research and Development Office, Department of Health and Social Services, Northern Ireland; and the Ulster Cancer Foundation.
Antimetabolite drugs such as 5-fluorouracil that are fluorinated derivatives of pyrimidines.
An anticancer drug that inhibits DNA topoisomerase I. It is used in the treatment of advanced colorectal cancer.
A platinum-based DNA-damaging anticancer drug that is used in the treatment of advanced colorectal cancer.
- DNA MICROARRAY
A technique that allows global changes in gene expression to be assessed.
- PREDICTIVE BIOMARKERS
Molecular markers that predict tumour sensitivity to chemotherapy.
Family of essential vitamins that act as cofactors in one-carbon transfer reactions.
- TERNARY COMPLEX
A stable complex that is formed between 5-fluorouracil, thymidylate synthase and 5,10-methylene tetrahydrofolate, and that blocks synthesis of thymidylate by the enzyme.
(Ribosomal RNA). The RNA component of ribosomes, which translate mRNA into protein.
(Transfer RNA). tRNAs bond with amino acids and transfer them to the ribosomes, where proteins are assembled according to the genetic code that is carried by mRNA.
(Small nuclear RNA). Small nuclear RNAs have key roles in the splicing of pre-mRNA into mature mRNA.
(Messenger RNA). RNA that serves as a template for protein synthesis.
- POLYADENYLATION OF mRNA
Mature mRNAs have a homopolymer of adenosine residues (poly(A) tails) at their 3′-termini, which are important in regulating their stability and translation.
Addition of glutamate residues to folates by folylpolyglutamate synthase (FPGS), increasing their intracellular retention. Most folate-dependent enzymes have a higher affinity for the polyglutamate forms of their folate cofactors.
Occurrence of variant DNA sequences in a population at frequencies that are too high to be due to random mutations.
- MICROSATELLITE INSTABILITY
Microsatellite instability refers to variations in the numbers of repetitive di-, tri- and tetranucleotide repeats (called microsatellites) found in DNA.
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Longley, D., Harkin, D. & Johnston, P. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3, 330–338 (2003). https://doi.org/10.1038/nrc1074
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