Investigational New Drugs

, Volume 18, Issue 4, pp 299–313 | Cite as

5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical Development

  • Jean L. Grem


5-Fluorouracil (5-FU) and 5-fluoro-2′-deoxyuridine (FdUrd) are pyrimidine analogs that have been partof the therapeutic armamentarium for a variety of solid tumorsfor over forty years. 5-FU has customarily required intravenousadministration due to poor and erratic oral bioavailability,while FdUrd has generally been employed for regionaladministration to the liver or the peritoneal cavity. A greatdeal of knowledge has been gained concerning the cellularpharmacology and mechanism of action of 5-FU since it was firstsynthesized in the late 1950's. A more thorough understanding ofthe factors influencing the metabolic activation of 5-FU and itscellular effects has generated considerable interest in combiningit with both modulatory agents such as leucovorin andmethotrexate that enhance its metabolism or cytotoxic effects.In addition, 5-FU has also been employed to enhance thetherapeutic activity of other antineoplastic agents or modalitiessuch as cisplatin and ionizing radiation with which it cansynergize. Appreciation of the clinical pharmacology of 5-FU andFdUrd have led to a variety of schedules that are clinicallyuseful. The preelinical and clinical pharmacology of 5-FU isreviewed to provide a basis for exploring the novel approachesto permit oral administration of 5-FU or its prodrugs that willbe described in other articles in this issue.

antimetabolites pyrimidine analogs thymidylate synthase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rutman RJ, Cantarow A, Paschkis KE: Studies on 2-acetylaminofluorene carcinogenesis: III. The utilization of uracil-2-C 14 by pre-neoplastic rat liver. Cancer Res 14: 119–126, 1954Google Scholar
  2. 2.
    Heidelberger C, Chaudhuari NK, Daneberg P, Mooreh D, Griesbach L, Duschinsky K Schnitzer RJ, Pleven E: Fluorinated pyrimidines. A new class of tumor inhibitory compounds. Nature 179: 663–666, 1957Google Scholar
  3. 3.
    Grem JL: 5-Fluorinated pyrimidines. In: Chabner BA, Longo, DL (eds) Cancer Chemotherapy and Biotherapy. Principles and Practice. Philadelphia, Lippincott-Raven Publishers, 1996, pp 149–210Google Scholar
  4. 4.
    Miyadera K, Sumizawa T, Haraguchi M, Yoshida H, Konstanty W, Yamada Y, Akiyama S: Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res 55: 1687–1690, 1995Google Scholar
  5. 5.
    Santi DV, McHenry CS, Sommer A: Mechanisms of interactions of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13: 471–474, 1974Google Scholar
  6. 6.
    Sommer A, Santi DV: Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5'-fluoro-2'-deoxyuridylate and methylene tetrachloride. Biochem Biophys Res Commun 57: 689–695, 1974Google Scholar
  7. 7.
    Santi DV, McHenry CS, Raines RT, Ivanetich KM: Kinetics and thermodynamics of the interaction of 5-fluouro-20-deoxyuridylate and thymidylate synthase. Biochemistry 26: 8606–8613 1987Google Scholar
  8. 8.
    Ulman B, Lee M, Martin DW Jr, Santi DV: Cytotoxicity of 5-fluoro-20-deoxyuridine: Sci USA 75: 980–983 1978Google Scholar
  9. 9.
    Radparvar S, Houghton PJ, Houghton JA: 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, 1989Google Scholar
  10. 10.
    Grem JL, Hoth D, Hamilton MJ, King, SA Leyland-Jones B: An overview of the current status and future directions of clinical trials of 5-fluorouracil and folinic acid. Cancer Treat Rep 71: 1249–1264, 1987Google Scholar
  11. 11.
    Howell SB, Mansfield SJ, Taetle R: Significance of variation in serum thymidine concentration for the marrow toxicity of methotrexate. Cancer Chemother Pharmacol 5: 221–226, 1981Google Scholar
  12. 12.
    Grem JL, Mulcahy RT, Miller EM, Allegra CJ, Fischer PH: Interaction of deoxyuridine with fluorouracil and dipyridamole in a human colon cancer cell line. Biochem Pharmacol 38: 51–59, 1989Google Scholar
  13. 13.
    Curtin NJ, Harris AL, Aherne GW: Mechanism of cell death following thymidylate synthase inhibition: 2'-deoxy-5'-triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole. Cancer Res 51: 2346–2352, 1991Google Scholar
  14. 14.
    Aherne GW, Hardcastle A, Raynaud F, Jackman AL: Immunoreactive dUMP and TTP pools as an index of thymidylate synthase inhibition; effect of tomudex (ZD 1694) and a nonpolyglutamated quinazoline antifolate (CB30900) in L1210 mouse leukaemia cells. Biochem Pharmacol 51: 1293–1301, 1996Google Scholar
  15. 15.
    Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH: Preclinical and Phase I clinical studies with the non-classical antifolate thymidylate synthase iahlbitor nolatrexed dlhydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol 16: 1131–1141, 1998Google Scholar
  16. 16.
    O'Dwyer PJ, Laub PB, DeMaria D, Qian M, Reilly D, Giantonio B, Johnston AL, Wu EY, Bauman L, Clendeninn NJ, Gallo JM: Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. Clin Cancer Res 2: 1685–1692, 1996Google Scholar
  17. 17.
    Harris JM, Mclntosh EM, Muscat GE: Structure/function analysis of a dUTPase: catalytic mechanism of a potential chemotherapeutic target. J Mol Biol 2: 275–287, 1999Google Scholar
  18. 18.
    Canman CE, Lawrence TS, Shewach DS, Tang HY, Maybaum J: Resistance to fluorodeoxyuridine-induced DNA damage and cytotoxicity correlates with an elevation of deoxyuridine triphosphatase activity and failure to accumulate deoxyuridine triphosphate. Cancer Res 53: 5219–5224, 1993Google Scholar
  19. 19.
    Mauro DJ, De Riel JK, Tallarida RJ, Sirover MA: Mechanisms of excision of 5-fluorouracil by uracil DNA glycosylase in normal human cells. Mol Pharmacol 43: 854–857, 1993Google Scholar
  20. 20.
    Wurzer JC, Tallarida RJ, Sirover MA: New mechanism of action of the cancer chemotherapeutic agent 5-fluorouracil in human cells. J Pharmacol Exp Ther 269: 39–43, 1994Google Scholar
  21. 21.
    Yoshioka A, Tanaka S, Hiraoka 0, Koyama Y, Hirota Y, Ayusawa D, Seno T, Garret C, Wataya Y: Deoxyribonucleoside triphosphate imbalance-fluorodeoxyuridine-induced DNA double strand breaks in mouse FM3A cells and the mechanism of cell death J Biol Chem 262: 8235–8241, 1987Google Scholar
  22. 22.
    Houghton JA, Tillman DM, Harwood FG: 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, 1995Google Scholar
  23. 23.
    Wadler S, Horowitz R, Mao X, Schwartz EL: Effect of interferon of 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks. Cancer Chemother Pharmacol 38: 529–535, 1996Google Scholar
  24. 24.
    Jones S, Willmore E, Durkacz BW: The effects of 5-fluoropyrimidines on nascent DNA synthesis in Chinese hamster ovary cells monitored by pH-step alkaline and neutral elution. Carcinogenesis 15: 2435–2438, 1994Google Scholar
  25. 25.
    Ismail A-SA, Van Groeningen CJ, Hardcastle A, Ren Q-F, Aherne GW, Geoffroy F, Allegra CJ, Grem JL: Modulation of fluorouracil cytotoxicity by interferons α and γ Mol Pharmacol 53: 252–261, 1998 Ayusawa D, Arai H, Wataya Y, Sento T: A specialized forrn of ehromosomal DNA degradation induced by thymidylate stress in mouse FM3A cells. Mutat Res 200: 221–230, 1988Google Scholar
  26. 26.
    Ayusawa D, Arai H, Wataya Y, Sento T: A specialized form of chromosomal DNA degradation induced by thymidylate stress in mouse FM3A cells. Mutat Res 200: 221–230, 1988Google Scholar
  27. 27.
    Canman CE, Tang HY, Normolle DP, Lawrence TS, Maybaum J: Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: Implications for mechanisms of resistance and cytotoxicity. Proc Natl Acad Sci USA 89: 10474–10478, 1992Google Scholar
  28. 28.
    Li Z-R, Yin M-B, Arredendo MA, SchŤber C, Rustum YM: Down-regulation of c-myc gene expression with induction of high molecular weight DNA fragments by fluorodeoxyuridine. Biochem Pharmacol 48: 327–334, 1994Google Scholar
  29. 29.
    Ren QT, Kao V, Grem J. Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2'-deoxyuridine in HT29 colon cancer cells. Clin Cancer Res 4: 2811–2818, 1998Google Scholar
  30. 30.
    Catchpoole DR, Stewart BW: Etoposide-induced cytotoxicity in two human T-cell leukemic lines: Delayed loss of membrane permeability rather than DNA fragmentation as an indicator of programmed cell death. Cancer Res 53: 4287–4296, 1993Google Scholar
  31. 31.
    Darzynkiewicz, Z. Methods in analysis of apoptosis and cell necrosis. In: Parker J, Stewart C (Eds) The Purdue Cytometry CD-ROM Vol 3, Purdue University, West Lafayette, 1997 [ISBN 1–890473–02–2]Google Scholar
  32. 32.
    Lowe SW, Ruley HE, Jacks T, Housman DE: p53-Dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74: 957–967, 1993Google Scholar
  33. 33.
    Fisher TC, Milner AE, Gregory CD, Jackman AL, Aherne GW, Hartley JA, Dive C, Hickman JA: Bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res 53: 3321–3326, 1993Google Scholar
  34. 34.
    Houghton JA, Harwood FG, Tillman DM: Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc Natl Acad Sci USA 94: 8144–8149, 1997Google Scholar
  35. 35.
    Tillman DM, Petak I, Houghton JA: A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 5: 425–430, 1999Google Scholar
  36. 36.
    Rode W, Scanlon KJ, Moroson BA, Bertino JR: Regulation of thymidylate synthetase in mouse leukemia cells (L 12 10). J Biol Chem 255: 1305–1311, 1980Google Scholar
  37. 37.
    Jenh C-H, Rao LG, Johnson LF: Regulation of thymidylate synthase enzyme synthesis in 5-fluorodeoxyuridine-resistant mouse fibroblasts during the transition from the resting to growing state. J Cell Physiol 122: 149–154, 1985Google Scholar
  38. 38.
    Cadman E, Heimer R: Levels of thymidylate synthetase during normal culture growth of L1210 cells. Cancer Res 46: 1195–1198, 1986Google Scholar
  39. 39.
    Chu E, Zinn S, Boarman D, Allegra CJ: Interaction of interferon and 5-fluorouracil in the H630 human colon carcinoma cell line. Cancer Res 50: 5834–5840, 1990Google Scholar
  40. 40.
    Van der Wilt CL, Pinedo HM, Smid K, Peters GJ: Elevation of thymidylate synthase following 5-fluorouracil treatment is prevented by the addition of leucovorin in murine colon tumors. Cancer Res 52: 4922–4928, 1992Google Scholar
  41. 41.
    Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC, Zinn S, Allegra CJ: Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci USA 88: 8977–8981, 1991Google Scholar
  42. 42.
    Chu E, Koeller DM, Johnston PG, Zinn S, Allegra CJ: Regulation of thymidylate synthase in human colon cancer cells treated with 5-fluorouracil and interferon-gamma. Mol Pharmacol 43: 527–533, 1993Google Scholar
  43. 43.
    Swain SM, Lippman ME, Chabner BA, Drake JC, Steinberg SM, Allegra CJ: Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 7: 890–899, 1989Google Scholar
  44. 44.
    Alexander HR, Grem JL, Hamilton JM, Pass HI, Hong M, Fraker DL, Steinberg SM, McAtee N, Allegra CJ, Johnston PG: Thymidylate synthase protein expression association with response to neoadjuvant chemotherapy and resection for locally advanced gastric and gastroesophagcal adcnocarcinoma. Cancer J 1: 49–54, 1995Google Scholar
  45. 45.
    Glazer RI, Lloyd LS: Association of cell lethality with incorporation of 5-fluorourauil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture. Mol Pharmacol 21: 468–473, 1982Google Scholar
  46. 46.
    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, 1986Google Scholar
  47. 47.
    Will CL, Dolnick BJ: 5-fluorouracil inhibits dihydrofolate reductase precursor mRNA processing and/or nuclear mRNA stability in methotrexate-resistant KB cells. J Biol Chem 264: 21413–21421, 1989Google Scholar
  48. 48.
    Armstrong RD, Lewis M, Stem SG, Cadman EC: Acute effect of 5-fluorouracil on cytoplasmic and nuclear dihydrofolate reductase messenger RNA metabolism. J Biol Chem 261: 7366–7371, 1986Google Scholar
  49. 49.
    Ghoshal K, Jacob ST: Specific inhibition of pre-ribosomal RNA processing in extracts from the lymphosarcoma cells treated with 5-fluorouracil. Cancer Res 54: 632–636, 1994Google Scholar
  50. 50.
    Ghoshal K, Jacob ST: An alternative molecular mechanism of action of 5-fluorouracil a potent anticancer drug. Biochem Pharmacol 53: 1569–1575, 1997Google Scholar
  51. 51.
    Danenberg PV, Shea LCC, Danenberg K: Effect of 5-fluorotiracil substitution on the self-splicing activity of Tetrahymena ribosomal RNA. Cancer Res 50: 1757–1763, 1990Google Scholar
  52. 52.
    Takimoto CH, Voeller DB, Strong JM, Anderson L, Chu E, Allegra CJ: Effects of 5-fluorouracil substitution on the RNA conformation and in vitro translation of thymidylate synthase messenger RNA. J Biol Chem 28: 21438–21422, 1993Google Scholar
  53. 53.
    Schmittgen TD, Danenberg KD, Horikoshi T, Lenz HJ, Danenberg PV: Effect of 5-fluoro and 5-bromouracil substitution on the translation of human thymidylate synthase mRNA. J Biol Chem 269: 16269–16275, 1994Google Scholar
  54. 54.
    Santi DV, Hardy LW: Catalytic mechanism and inhibition of tRNA Uracil-5-methyltransferase: evidence for covalent catalysis. Biochemistry 26: 8599–8606, 1987Google Scholar
  55. 55.
    Samuelsson T: Interactions of transfer RNA pseudouridine synthases with RNAs substituted with fluorouracil. Nucleic Acids Res 19: 6139–6144, 1991Google Scholar
  56. 56.
    Geoffroy FJ, Allegra CJ, Singha B, Grem JL: Enhanced cytotoxicity with interleucin-1α and 5-fluorouracil in HCT116 colon cancer cells. Oncol Res 6: 581–591, 1994Google Scholar
  57. 57.
    Fujishima H, Niho Y, Kondo T, Tatsumoto T, Esaki T, Masumoto N, Nakano S: Inhibition by 5-fluorouracil of ERCC1 and gamma-glutamylcysteine synthetase messenger RNA expression in a cisplatin-resistant HST-1 human squamous carcinoma cell line. Oncol Res 9: 167–172, 1997Google Scholar
  58. 58.
    Jin Y, Heck DE, DeGeorge G, Tian Y, Laskin JD: 5-fluorouracil suppresses nitric oxide biosynthesis in colon carcinoma cells. Cancer Res 56: 1978–1982, 1996Google Scholar
  59. 59.
    Doong SL, Dolnick BJ: 5-Fluorouracil substitution alters premRNA splicing in vitro. J Biol Chem 263: 4467–4473, 1988Google Scholar
  60. 60.
    Patton JR: Ribonucleoprotein particle assembly and modification of U2 small nuclear RNA containing 5-fluorouridine. Biochemistry 32: 8939–8944, 1993Google Scholar
  61. 61.
    Wu XP, Dolnick BJ: 5-fluorouracil alters dihydrofolute reductase pre-mRNA splicing as determined by quantitative polymerase chain reaction. Mol Pharmacol 44: 22–29, 1993Google Scholar
  62. 62.
    Lenz H-J, Manno DJ, Danenberg KD, Danenberg PV: Incorporation of 5-fluorouracil into U2 and U6 snRNA inhibits mRNA precursor splicing. J Biol Chem 269: 31962–31968, 1994Google Scholar
  63. 63.
    Pritchard DM, Watson AJM, Potten CS, Jackman AL, Hickman JA. Inhibition of undine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation. Proc Natl Acad Sci USA 94: 1795–1799, 1997Google Scholar
  64. 64.
    Johnston PG, Lenz H-J, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L: 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, 1995Google Scholar
  65. 65.
    Lenz H-J, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Garcia Y, Li J, Leichman L: Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. J Clin Oncol 14: 176–182, 1995Google Scholar
  66. 66.
    Leichman CG, Lenz H-, Leichman L, Danenberg K, Baranda J, Groshen S, Boswell W, Metzger R, Tan M, Danenberg PV: Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted infusion fluorouracil and weekly leucovorin. J Clin Oncol 15: 3223–3229, 1997Google Scholar
  67. 67.
    Aschele C, Sobrero A, Faderan MA, Bertino JR: Novel mechanisms of resistance to 5-fluorouracil in human colon eancer (HCT-8) sublines following exposure to two different clinically relevant dose schodules. Cancer Res 52: 1855–1864, 1992Google Scholar
  68. 68.
    Sobrero AF, Aschele C, Guglielmi AP, Mori AM, Melioli GG, Rosso R, Rertino JR: Synergism and lack of crossresistance between short-term and continuous exposure to fluorouracil in human colon adenocarcinoma cells. J Natl Cancer Inst 85: 1937–1944, 1993Google Scholar
  69. 69.
    Sobrero AF, Aschele C, Bertino JR: Fluorouracil in colorectal cancer-a tale of two drugs: implications for biochemical modulation. J Clin Oncol 15: 368–381, 1997Google Scholar
  70. 70.
    Evans RM, Laskin JD, Hakala MT: Assessment of growthlimiting events caused by 5-fluorouracil in mouse cells and in human cells. Cancer Res 40: 4113–4122, 1980Google Scholar
  71. 71.
    Ren Q-T, Van Groeningen CJ, Geoffroy F, Allegra CJ, Johnston PG, Grem JL: Determinants of cytotoxicity with prolonged exposure to fluorouracil in human colon cancer cells. Oncol Res 9: 77–88, 1997Google Scholar
  72. 72.
    Thirion P, Cunningham D, Findlay M, Norman A, Falcone A, Logue JP, Tralongo P, Aschele C, Piedbois P: Pooled analysis of phase II trials with low-dose 5-fluorouracil continuous infusion as a second line chemotherapy in advanced colorectal cancer. Proc Am Soc Clin Oncol 17: 272a, 1998 (abstr 1047)Google Scholar
  73. 73.
    Nobile MT, Barzacch MC, Sanguineti O, Chiara S, Gozza A, Vincenti M, Lavarello A, Cognein P, Lionetto R, Percivale PL, Bertoglio S, Murolo C, Esposito M, Vannozzi MO, Rosso R: Activity of high dose 24 hour 5-fluorouracil infusion plus l-leucovorin in advanced colorectal cancer. Anticancer Res 18: 517–521, 1998Google Scholar
  74. 74.
    de Gramont A, Bosset JF, Milan C, Rougier P, Bouche 0, Etienne PL, Morvan F, Louvet C, Guillot T, Francois E, Bedenne L: Randomized trial comparing montbly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 15: 808–815, 1997Google Scholar
  75. 75.
    MacMillan WE, Wolberg WH, Welling PG: Pharmacokinetics of fluorouracil in humans. Cancer Res 39: 3479–3492, 1978Google Scholar
  76. 76.
    Heggie GD, Sommadossi J-P, Cross DS, Huster WJ, Diasio RB: Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47: 2203–2206, 1987Google Scholar
  77. 77.
    van Groeningen CJ, Pinedo HM, Heddes J, Kok RM, de Jong AP, Wattel E, Peters GJ, Lankelma J: Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule. Cancer Res 48: 6956–6961, 1988Google Scholar
  78. 78.
    Grem JL, McAtee N, Balis FM, Murphy RF, Steinberg, S Gay L, Caubo K, Hamilton M, Sorenson M, Sartor 0, Goldstein L, Goldspiel B, Allegra CJ: A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol 9: 1811–1820, 1991Google Scholar
  79. 79.
    Grem JL, McAtee N, Murphy RF, Balis FM, Steinberg S, Hamilton JM, Arbuck SG, Setser A, Jordan E, Chen A, Kohler D, Kotite B, Allegra, CJ: Doseintensification of 5-fluorouracil/high-dose leucovorin with granulocyte-macrophage colony stimulating factor in metastatic gastrointestinal cancer. J Clin Oncol 12: 560–568, 1994Google Scholar
  80. 80.
    Harris BE, Song R, Soong SJ, Diasio RB: Relationship between dihydropyrinlidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 50: 197–201, 1990Google Scholar
  81. 81.
    Yoshida T, Araki E, ligo M, Fujii T, Yoshino M, Shiniada Y, Saito D, Tajiti H, Yaniaguchi H, Yoshida S, et al: Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer. Cancer Chemother Pharmacol 26: 352–354, 1990Google Scholar
  82. 82.
    Grem JL, McAtee N, Balis F, Murphy R, Venzon D, Kramer B, Goldspiel B, Begley M, Allegra CJ: A phase II study of continuous infusion 5-fluorouracil and leucovorin with weekly cisplatin in metastatic colorectal carcinoma. Cancer 72: 663–668, 1993Google Scholar
  83. 83.
    Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK: Pharmacokineties of 5-fluorouracil administered orally by rapid intravenous and by slow infusion. Cancer Res 40: 2223–2228, 1980Google Scholar
  84. 84.
    Petit E, Milano G, Levi F, Thyss A, Bailleul F, Schneider M: Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients. Cancer Res 48: 1976–1980, 1988Google Scholar
  85. 85.
    Fleming RF, Milano G, Thyss A, Etienne MC, Renee N, Schneider M, Demard F: Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 52: 2899–2902, 1992Google Scholar
  86. 86.
    Erlichman C, Fine S, Elhakim T: Plasma pharmacokinetics or 5-FU given by continuous infusion with allopurinol. Cancer Treat Rep 70: 903–904, 1986Google Scholar
  87. 87.
    Remick SC, Grem JL, Fischer PH, Tutsch KD, Alberti DB, Nieting LM, Tombes MB, Bruggink J, Willson JK.V, Trump DL: Phase I trial of 5-fluorouracil and dipyridamole administered by 72-hour concurrent continuous infusion. Cancer Res 50: 2667–2672, 1990Google Scholar
  88. 88.
    Grem JL, McAtee N, Steinherg SM, Murphy R, Drake J, Chisena T, Hamilton JM, Arbuck S, Balis F, Cysyk R, Goldstein L, Sorensen JM, Chen A, Setser A, Jordan E, Goldspiel B, Carvalho M, Allegra CJ: A phase I study of continuous infusion 5-fluorouracil plus calcium leucovorin in combination with n-(phosphonacetyl)-L-aspartate in metastatic gastrointestinal adenocarcinoma. Cancer Res 53: 4828–4836, 1993Google Scholar
  89. 89.
    Collins JM, Dedrick RL, King FG, Speyer JL, Myers CE: Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. Clin Pharmacol Ther 28: 235–246, 1980Google Scholar
  90. 90.
    McDermott BJ, van der Berg HW, Murphy RF: Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. Cancer Chemother Pharmacol 9: 173–178, 1982Google Scholar
  91. 91.
    Schwartz PM, Turek PJ, Hyde CM, Cadman EC, Handschumacher RE: Altered plasma kineties of 5-FU at high dosage in rat and man. Cancer Treat Rep 69: 133–136, 1985Google Scholar
  92. 92.
    Wagner JG, Gyves JW, Stetson PL, Walker-Andrews SC, Wollner IS, Cochran MK, Ensminger WU: Steady-state non312 linear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients. Cancer Res 46: 1499–1506, 1986Google Scholar
  93. 93.
    Ensminger WD, Rosowsky A, Raso VO, Levin DC, Glode M, Come S, Steele G, Frei E 3rd: A clinical pharmacological evaluation of hepatic arterial infusion of 5-fluoro-2'-deoxyuridine and 5-fluorouracil. Cancer Res 38: 3784–3792, 1978Google Scholar
  94. 94.
    Goldberg JA, Kerr DJ, Watson DG, Willmott N, Bates CD, McKillop JH, McArdle CS: The pharmacokineties of 5-fluorouracil administered by arterial infusion in advanced colorectal hepatic metastases. Br J Cancer 61: 913–915, 1990Google Scholar
  95. 95.
    Cohen JL, Irwin LW, Marshall OJ, Darvey H, Baternan JR: Clinical pharmacology of oral and intravenous 5-fluorouracil (NSC-19893). Cancer Chemother Rep 58: 723–731, 1974Google Scholar
  96. 96.
    Hahn RG, Moertel CG, Schutt AJ, Bruckner HW: A doubleblind comparison of intensive course 5-fluorouracil by oral vs intravenous route in the treatment of colorectal carcinoma. Cancer 35: 1031–1035, 1975Google Scholar
  97. 97.
    Christophidis N, Vajda FJE, Lucas I, Louis W: Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokinet 3: 330–336, 1978Google Scholar
  98. 98.
    Finch RE, Bending MR, Lant AF: Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. Br J Clin Pharmacol 7: 613–617, 1979Google Scholar
  99. 99.
    Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK: Pharmacokinetics of 5-fluorouracil administered orally by rapid intravenous, and by slow infusion. Cancer Res 40: 2223–2228, 1990Google Scholar
  100. 100.
    Almersjo OE, Gustavsson BG, Regardh CG, Wahlen P: Pharmacokinetie studies of 5-fluorouracil after oral and intravenous administration in man. Acta Pharmacol Toxicol 46: 329–336, 1980Google Scholar
  101. 101.
    Thyss A, Milano G, Renee N, Vallicioni J, Schneider M, Demard F: Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer. Cancer Chemother Pharmacol 16: 64–66, 1986Google Scholar
  102. 102.
    Trump DL, Egorin MJ, Forrest A, Willson JK, Remick S, Tutsch KD: Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridarnole. J Clin Oncol 9: 2027–2035, 1991Google Scholar
  103. 103.
    Santini J, Milano G, Thyss A, Renee N, Viens P, Ayela P, Schneider M, Demard F: 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br J Cancer 59: 287–290, 1989Google Scholar
  104. 104.
    Fety R, Rolland F, Barberi-Heyob M, Hardouin A, Campion L, Conroy T, Merlin J-L, Rivière: A, Perrocheau G, Etienne M-C, Milano G: Clinical impact of pharmacokineticallyguided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 4: 2039–2045, 1998Google Scholar
  105. 105.
    Fleming GF, Schilsky RL, Mick R, O'Brien SM, Vogelzang NJ, Ratain MJ: Circadian variation of 5-fluorouracil plasma levels during continuous infusion 5-FU and leucovorin in patients with hepatic or renal dysfunction. Ann Oncol 5(suppl 5): 236, 1994 (abstr).Google Scholar
  106. 106.
    Takimoto CH, Yee LK, Venzon D, Schuler B, Grollman F, Chabuk C, Hamilton JM, Chen AP, Allegra CJ, Grem J: High inter-and intrapatient variation in 5-fluorouracil plasma concentrations during a prolonged drug infusion. Clin Cancer Res (In Press, 1999)Google Scholar
  107. 107.
    Grem JL, Yee LK, Venzon DJ, Takimoto CH, Allegra CJ: Inter-and intraindividual variation in dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Cancer Chemother Pharmacol 40: 117–125, 1997Google Scholar
  108. 108.
    Levi FA, Zidani R, Vannetzul JM, Perpoint B, Focan C, Faggiuolo R, Chollet P, Garufi C, Itzhaki M, Dogliotti L: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinie acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst 86: 1608–1617, 1994Google Scholar
  109. 109.
    Uvi F, Zidani R, Misset J-L: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350: 681–686, 1997Google Scholar
  110. 110.
    Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NK: Age and sex are independent predictors of 5-fluorouracil toxicity. Cancer 75: 11–17, 1995Google Scholar
  111. 111.
    Zalcberg J, Kerr D, Seymour L, Palmer M: Haematological and non-haematological toxieity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number. Tomudex International Study Group. Eur J Cancer 34: 1871–1875, 1998Google Scholar
  112. 112.
    Tepper JE, O'Connell MJ, Petroni GR, Hollis D, Cooke E, Benson AB 3rd, Cummings B, Gunderson LL, Macdonald JS, Martenson JA: Adjuvant post-operative fluorouracilmodulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol 15: 2030–2039, 1997Google Scholar
  113. 113.
    Meta-Analysis Group In Cancer: Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 16: 3537–3541, 1988Google Scholar
  114. 114.
    Tuchman M, Roemeling RV, Hrushesky WAM, Sothern RB, O'Dea RF: Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells. Enzyme 42: 15–224, 1989Google Scholar
  115. 115.
    Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Santini J, Frenay M, Renee N, Schneider M, Demard F: Influence of sex and age on fluorouracil clearance. J Clin Oncol 10: 1171–1175, 1992Google Scholar
  116. 116.
    Lu A, Zhang R, Diasio RB: Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified de-ficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 53: 5433–5438, 1993Google Scholar
  117. 117.
    Lu A, Zhang R, Diasio RB: Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy. Clin Pharmacol Ther 58: 512–522, 1995Google Scholar
  118. 118.
    Fleming RA, Milano GA, Gaspard MH, Bargnoux PJ, Thyss A, Plagne R, Renee N, Schneider M, Demard F: Dihydropyrimidine dehydrogenase activity in cancer patients. Eur J Cancer 29A(5): 740–744, 1993Google Scholar
  119. 119.
    Tateishi T, Watanabe M, Nakura H, Tanaka M, Kumai T, Kobayashi S: Sex-orage-related differences were not detected in the activity of dihydropyrimidine dehydrogenase from rat liver. Pharmacol Res 35: 103–106, 1997Google Scholar
  120. 120.
    The 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, 1992Google Scholar
  121. 121.
    The Advanced Colorectal Cancer Meta-analysis Project: Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 12: 960–969, 1994Google Scholar
  122. 122.
    Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L, Emami B: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: 1593–1598, 1992Google Scholar
  123. 123.
    Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, Byhardt R, Russell AH, Beitler JJ, Spencer S, Asbell SO, Graham MV, Leichman LL: Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01). Radiation Therapy Oncology Group. J Am Med Assoc 281: 1623–1627, 1999Google Scholar
  124. 124.
    Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C Stevens RE, Rotman M, Gershenson DM: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340: 1137–1143, 1999Google Scholar
  125. 125.
    O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, Mayer RJ, Gunderson LL, Rich TA: Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 33: 502–507, 1994Google Scholar
  126. 126.
    UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: Results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin C. Lancet 348: 1049–1054, 1996Google Scholar
  127. 127.
    Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van Glabbeke M, Pierart M: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15: 2040–2049, 1997Google Scholar
  128. 128.
    Meta-Analysis Group In Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16: 301–308, 1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Jean L. Grem
    • 1
  1. 1.Cellular and Clinical Pharmacology Section, Developmental Therapeutics Department, National Cancer Institute-Medicine BranchNational Naval Medical CenterBethesdaUSA

Personalised recommendations