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Clinical Pharmacology of 5-Fluorouracil

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  • Drug Disposition
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Summary

5-Fluorouracil, first introduced as a rationally synthesised anticancer agent 30 years ago, continues to be widely used in the management of several common malignancies including cancer of the colon, breast and skin. This drug, an analogue of the naturally occurring pyrimidine uracil, is metabolised via the same metabolic pathways as uracil. Although several potential sites of antitumour activity have been identified, the precise mechanism of action and the extent to which each of these sites contributes to tumour or host cell toxicity remains unclear.

Several assay methods are available to quantify 5-fluorouracil in serum, plasma and other biological fluids. Unfortunately, there is no evidence that plasma drug concentrations can predict antitumour effect or host cell toxicity. The recent development of clinically useful pharmacodynamic assays provides an attractive alternative to plasma drug concentrations, since these assays allow the detection of active metabolites of 5-fluorouracil in biopsied tumour or normal tissue.

5-Fluorouracil is poorly absorbed after oral administration, with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). Recently, studies have demonstrated the pharmacokinetic rationale and clinical feasibility of hepatic arterial infusion and intraperitoneal administration of 5-fluorouracil. In addition, 5-fluorouracil continues to be used in topical preparations for the treatment of malignant skin cancers.

Following parenteral administration of 5-fluorouracil, there is rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes. The rapid elimination is primarily due to swift catabolism of 5-fluorouracil in the liver.

As with all drugs, caution should be used in administering 5-fluorouracil in various pathophysiological states. In general, however, there are no set recommendations for dose adjustment in the presence of renal or hepatic dysfunction. Drug interactions continue to be described with other antineoplastic drugs, as well as with other classes of agents.

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References

  • Ambre JJ, Fischer LJ. The effect of prednisone and other factors on the catabolism of 5-fluorouracil in rats. Journal of Laboratory and Clinical Medicine 78: 343–353, 1971

    PubMed  CAS  Google Scholar 

  • Ardalan B, Buscaglia MD, Schein PS. Tumor 5-fluorodeoxyuridylate concentrations as a determinant of 5-fluorouracil response. Biochemical Pharmacology 27: 2009–2013, 1978

    Article  PubMed  CAS  Google Scholar 

  • Armstrong RD, Lewis M, Stern SG, Cadman EC. Acute effect of 5-fluorouracil on cytoplasmic and nuclear dihydrofolate reductase messenger RNA metabolism. Journal of Biological Chemistry 261: 7366–7371, 1986a

    PubMed  CAS  Google Scholar 

  • Armstrong RD, Takimoto CH, Cadman EC. Fluoropyrimidine-mediated changes in small nuclear RNA. Journal of Biological Chemistry 261: 21–24, 1986b

    PubMed  CAS  Google Scholar 

  • Au JL, Rustum YM, Ledesma EJ, Mittelman A, Greaven PJ. Clinical pharmacological studies of concurrent infusion of 5-fluorouracil and thymidine in treatment of colorectal carcinoma. Cancer Research 42: 2930–2937, 1982

    PubMed  CAS  Google Scholar 

  • Aubert C, Luccioni C, Coassolo P, Sommadossi JP, Cano JP. Comparative determination of 5-fluorouracil in plasma using GC/MS and HPLC. Arzneimittel-Forschung 31: 2048–2053, 1981

    PubMed  CAS  Google Scholar 

  • Aubert C, Sommadossi JP, Coassolo P, Cano JP, Rigault JP. Quantitative analysis of 5-fluorouracil and 5,6-dihydrofluorouracil in plasma by gas chromatography mass spectrometry. Biomedical Mass Spectrometry 9: 336–339, 1982

    Article  PubMed  CAS  Google Scholar 

  • Balch CM, Levin B. Regional and systemic chemotherapy for colorectal metastases to the liver. World Journal of Surgery 11: 521–526, 1987

    Article  PubMed  CAS  Google Scholar 

  • Bardkji Z, Jolivet J, Langelier Y, Besner JG, Ayoub J. 5-Fluorouracil-metronidazole combination therapy in metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology 18: 140–144, 1986

    Google Scholar 

  • Beck WT. The cell biology of multiple drug resistance. Biochemical Pharmacology 36: 2879–2887, 1987

    Article  PubMed  CAS  Google Scholar 

  • Bender RA, Zwelling LA, Doroshow JH, Myers CE, Chabner BA, et al. Antineoplastic drugs: clinical pharmacology and therapeutic use. Drugs 16: 46–87, 1978

    Article  PubMed  CAS  Google Scholar 

  • Berger SH, Jenh CH, Johnson LF, Berger FG. Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Molecular Pharmacology 28: 461–467, 1985

    PubMed  CAS  Google Scholar 

  • Bertino JR, Sawicki WL, Linquist CA, et al. Schedule-dependent antitumor effects of methotrexate and 5-fluorouracil. Cancer Research 37: 327–328, 1977

    PubMed  CAS  Google Scholar 

  • Bowen D, White JC, Goldman ID. A basis for fluoropyrimidine-induced antagonism to methotrexate in Ehrlich ascites tumor cells in vitro. Cancer Research 38: 219–222, 1978

    PubMed  CAS  Google Scholar 

  • Buckpitt AR, Boyd MR. A sensitive method for determination of 5-fluorouracil and 5-fluoro-2′-deoxyuridine in human plasma by high-pressure liquid chromatography. Analytical Biochemistry 106: 432–437, 1980

    Article  PubMed  CAS  Google Scholar 

  • Cadman E, Hermer R, Davis L. Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism. Science 205: 1135–1137, 1979

    Article  PubMed  CAS  Google Scholar 

  • Cano JP, Aubert C, Rigault JP, Gilli R, Coassolo P, et al. Advantages and limitations of pharmacokinetic studies in the rationalization of anticancer therapy: methotrexate and 5-FU. Cancer Treatment Reports 65: 33–42, 1981

    PubMed  CAS  Google Scholar 

  • Cano JP, Rigault JP, Aubert C, Carcassione Y, Seitze JF. Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics. Bulletin du Cancer 66: 67–74, 1979

    PubMed  CAS  Google Scholar 

  • Caradonna SJ, Cheng YC. The role of deoxyuridine triphosphate nucleotidohydrolase, uracil-DNA glycosylase, and DNA polymerase α in the metabolism of FUdR in human tumor cells. Molecular Pharmacology 18: 513–520, 1980

    PubMed  CAS  Google Scholar 

  • Carter SK (Ed.). Chemotherapy of cancer, Wiley, New York, 1977

    Google Scholar 

  • Chabner BA. Pyrimidine antagonists. In Chabner BA (Ed.) Pharmacologic principles of cancer treatment, pp. 183–212, WB Saunders Co., Philadelphia, 1982

    Google Scholar 

  • Chadwick M, Chang C. Comparative physiologic dispositions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil in mice bearing solid L1210 lymphocytic leukemia. Cancer Treatment Reports 60: 845–855, 1976

    PubMed  CAS  Google Scholar 

  • Chaudhuri NK, Mukherjee KL, Heidelberger C. Studies on fluorinated pyrimidines. VII. The degradative pathway. Biochemical Pharmacology 1: 328–341, 1959

    Article  Google Scholar 

  • Cheng YC, Nakayama K. Effects of 5-fluoro-2′-deoxyuridine on DNA metabolism in HeLa cells. Molecular Pharmacology 23: 171–174, 1983

    PubMed  CAS  Google Scholar 

  • Christophidis N, Mihaly G, Vajda F, Louis W. Comparison of liquid- and gas-liquid chromatographic assays of 5-fluorouracil in plasma. Clinical Chemistry 25: 83–86, 1979

    PubMed  CAS  Google Scholar 

  • Christophidis N, Vajda FJE, Lucas I, Drummer O, Moon WJ, et al. Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. Clinical Pharmacokinetics 3: 330–336, 1978

    Article  Google Scholar 

  • Clark JL, Berger SH, Mittelman A, Berger FG. Thymidylate synthase gene amplification in a colon tumor resistant to fluoropyrimidine chemotherapy. Cancer Treatment Reports 71: 261–265, 1987

    PubMed  CAS  Google Scholar 

  • Clarkson B, O’Connor A, Winston L, Hutchison D. The physiological disposition of 5-fluorouracil and 5-fluorodeoxyuridine in man. Clinical Pharmacology and Therapeutics 5: 581–610, 1964

    PubMed  CAS  Google Scholar 

  • Cohen JL, Irwin LE, Marshall GJ, Darvey H, Bateman JR. Clinical pharmacology of oral and intravenous 5-fluorouracil (NSC-19893). Cancer Chemotherapy Reports 58: 723–731, 1974

    CAS  Google Scholar 

  • Cohen MB, Glazer RI. Cytotoxicity and the inhibition of ribosomal RNA processing in human colon carcinoma cells. Molecular Pharmacology 27: 308–313, 1985

    PubMed  CAS  Google Scholar 

  • Collins JM, Dedrick RL, King FG, Speyer JL, Myers CE. Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes. Clinical Pharmacology and Therapeutics 28: 235–246, 1980

    Article  PubMed  CAS  Google Scholar 

  • Danenberg PV. The role of reduced folates in the enhanced binding of FdUMP to dTMP synthetase. In Bruckner & Rustum (Eds) The current status of 5-fluorouracil-leucovorin calcium combination, pp. 5–11, John Wiley & Sons, New York, 1984

    Google Scholar 

  • Danenberg PV, Danenberg KD. Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2′-deoxyuridylate from thymidylate synthetase: evidence for an ordered mechanism. Biochemistry 17: 4018–4024, 1978

    Article  PubMed  CAS  Google Scholar 

  • Danenberg PV, Heidelberger C, Mulkins MA, Peterson AR. The incorporation of 5-fluoro-2-deoxyuridine into DNA of mammalian tumor cells. Biochemical and Biophysical Research Communications 102: 654–658, 1981

    Article  PubMed  CAS  Google Scholar 

  • Danenberg PV, Lockshin A. Fluorinated pyrimidines as tight-binding inhibitors of thymidylate synthase. Pharmacological Therapeutics 13: 69–90, 1981

    Article  CAS  Google Scholar 

  • Dedrick R, Myers C, Bungay P, et al. Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treatment Reports 62: 1–11, 1978

    PubMed  CAS  Google Scholar 

  • DeLap RJ. The effect of leucovorin on the therapeutic index of fluorouracil in cancer patients. Yale Journal of Biology and Medicine 61: 23–34, 1988

    PubMed  CAS  Google Scholar 

  • DeVita VT, Hellman S, Rosenberg SA. (Eds). Cancer, principles and practice of oncology, 2nd ed., JB Lippincott Company, Philadelphia, 1985

    Google Scholar 

  • Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. Journal of Clinical Investigation 81: 47–51, 1988

    Article  PubMed  CAS  Google Scholar 

  • Diasio RB, Schuetz JD, Wallace HJ, Sommadossi JP. Dihydrofluorouracil, a fluorouracil catabolite with antitumor activity in murine and human cell. Cancer Research 45: 4900–4903, 1985

    PubMed  CAS  Google Scholar 

  • Diasio RB, Wilburn ME. Effect of column temperature on resolution of fluoropyrimidines by reverse phase high performance liquid chromatography. Journal of Chromatographic Science 17: 565–567, 1979

    CAS  Google Scholar 

  • Dolnick BJ, Pink JJ. 5-Fluorouracil modulation of dihydrofolate reductase RNA levels in methotrexate-resistant KB cells. Journal of Biological Chemistry 258: 13299–13306, 1983

    PubMed  CAS  Google Scholar 

  • Duschinsky R, Pleven E, Heidelberger C. The synthesis of 5-fluoropyrimidines. Journal of the American Chemical Society 79: 4559–4560, 1957

    Article  CAS  Google Scholar 

  • Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Seminars in Oncology 10: 176–182, 1983

    PubMed  CAS  Google Scholar 

  • Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, et al. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Research 38: 3784–3792, 1978

    PubMed  CAS  Google Scholar 

  • Erlichman C, Donehower RC, Speyer JL, Klecker R, Chabner BA. Phase I-phase II trial of N-phosphonacetyl-L-aspartic acid given by intravenous infusion and 5-fluorouracil given by bolus injection. Journal of the National Cancer Institute 68: 227–231, 1982

    PubMed  CAS  Google Scholar 

  • Evans RM, Laskin JD, Hakala MT. Effect of excess folates and deoxyinosine on the activity and site of actions of 5-fluorouracil. Cancer Research 41: 3288–3295, 1981

    PubMed  CAS  Google Scholar 

  • Finch RE, Bending MR, Lant AF. Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. British Journal of Clinical Pharmacology 7: 613–617, 1979

    Article  PubMed  CAS  Google Scholar 

  • Finn C, Sadee W. Determination of 5-fluorouracil (NSC-19893) plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemotherapy Reports 59: 279–286, 1975

    CAS  Google Scholar 

  • Fox RM, Woods RL, Tattersall MHN. Allopurinol modulation of high dose fluorouracil toxicity. Cancer Treatment Reports 6: 143–147, 1979

    Article  CAS  Google Scholar 

  • Fraile RJ, Baker LH, Buroker TR, Horwitz J, Vaitkevicius VK. Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion. Cancer Research 40: 2223–2228, 1980

    PubMed  CAS  Google Scholar 

  • Garrett ER, Hurst GH, Green JR. Kinetics and mechanisms of drug action on microorganisms. XXIII. Microbial kinetic assay for fluorouracil in biological fluids and its application to human pharmacokinetics. Journal of Pharmaceutical Sciences 66: 1422–1429, 1977

    Article  PubMed  CAS  Google Scholar 

  • Goldberg AR, Machledt JH Jr, Pardee AB. On the action of fluorouracil on leukemia cells. Cancer Research 26: 1611–1615, 1966

    PubMed  CAS  Google Scholar 

  • Grem J, Hoth D, Hamilton JM. Overview of current status and future direction of clinical trials with 5-fluorouracil in combination with folinic acid. Cancer Treatment Reports 12: 1249–1264, 1987

    Google Scholar 

  • Groeningen CJV, Leyva A, Kraal I, Peters GJ, Pinedo HM. Clinical and pharmacokinetic studies of prolonged administration of high-dose uridine intended for rescue from 5-FU toxicity. Cancer Treatment Reports 70: 745–750, 1986

    PubMed  Google Scholar 

  • Gyves J. Pharmacology of intraperitoneal infusion 5-fluorouracil and mitomycin-C. Seminars in Oncology 12: 29–32, 1985

    PubMed  CAS  Google Scholar 

  • Hakala MT. Basis for the effect of leucovorin on the activity and site of action of 5-fluorouracil in human cells. In Bruckner & Rustum (Eds) The current status of 5-fluorouracil-leucovorin calcium combination, pp. 33–39, John Wiley & Sons, New York, 1984

    Google Scholar 

  • Harris BE, Song R, He Y, Diasio RB. Circadian periodicity of dihydropyrimidine dehydrogenase (DPD) activity in humans: possible relevance to toxicity from fluoropyrimidine (FP) drugs with implications for FP infusion by programmable pumps. Proceedings of the American Society of Clinical Oncology 7: 77, 1988a

    Google Scholar 

  • Harris BE, Song R, He Y, Soong SJ, Diasio RB. Circadian rhythm of rat liver dihydropyrimidine dehydrogenase: possible relevance to fluoropyrimidine chemotherapy. Biochemical Pharmacology 37: 4759–4762, 1988b

    Article  PubMed  CAS  Google Scholar 

  • Harvey VJ, Slevin ML, Dilloway MR, Clark PI, Johnston A, et al. The influence of Cimetidine on the pharmacokinetics of 5-fluorouracil. British Journal of Clinical Pharmacology 18: 421–430, 1984

    Article  PubMed  CAS  Google Scholar 

  • Haynes HA, Mead KW, Goldwyn RM. Cancers of the skin. In DeVita et al. (Eds) Cancer, principles and practice of oncology, 2nd ed., pp. 1343–1369, J.B. Lippincott Co., Philadelphia, 1985

    Google Scholar 

  • Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB. Metabolism of 5-fluorouracil in cancer patients with quantitation of fluorouracil catabolites in plasma, urine, and bile over time. Cancer Research 47: 2203–2206, 1987

    PubMed  CAS  Google Scholar 

  • Heidelberger C. Fluorinated pyrimidines and their nucleosides. In Sartorelli & Johns (Eds) Antineoplastic and immunosuppressive agents, part II, pp. 193–231, Springer-Verlag, New York, 1975

    Chapter  Google Scholar 

  • Heidelberger C, Ghobar A, Baker RK, Mukherjee KL. Studies on fluorinated pyrimidines. X. In vivo studies on tumor resistance. Cancer Research 20: 897–902, 1960a

    PubMed  CAS  Google Scholar 

  • Heidelberger C, Kaldor G, Mukherjee KL, Danenberg PV. Studies on fluorinated pyrimidines. XI. In vitro studies on tumor resistance. Cancer Research 20: 905–909, 1960b

    Google Scholar 

  • Herrick D, Kufe DW. Lethality associated with incorporation of 5-fluorouracil into preribosomal RNA. Molecular Pharmacology 21: 468–473, 1982

    Google Scholar 

  • Herrick D, Kufe DW. Lethality associated with incorporation of 5-fluorouracil into preribosomal RNA. Molecular Pharmacology 26: 135–140, 1984

    PubMed  CAS  Google Scholar 

  • Hillcoat BL, McCulloch PB, Figueredo AT, Ehsan MH, Rosenfeld JM. Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion. British Journal of Cancer 38: 719–724, 1978

    Article  PubMed  CAS  Google Scholar 

  • Hohn D, Melnick J, Stagg R, Altman D, Friedman M, et al. Biliary sclerosis in patients receiving hepatic arterial infusions and floxuridine. Journal of Clinical Oncology 3: 98–102, 1985

    PubMed  CAS  Google Scholar 

  • Hohn DC, Rayner AA, Economou JS, Ignoffo RJ, et al. Toxicities and complications of implanted pump hepatic arterial infusions and intravenous floxuridine infusion. Cancer 57: 465–470, 1986

    Article  PubMed  CAS  Google Scholar 

  • Houghton JA, Houghton PJ. On the mechanism of cytotoxicity of fluorinated pyrimidines in four human colon adenocarcinoma xenografts maintained in immune-deprived mice. Cancer 45: 1159–1167, 1980

    Article  PubMed  CAS  Google Scholar 

  • Houghton JA, Houghton PJ. 5-Halogenated pyrimidines and their nucleosides. In Fox & Fox (Eds) Antitumor drug resistance, pp. 515–549, Springer-Verlag, New York, 1984

    Chapter  Google Scholar 

  • Howell SB, Wung WE, Taetle R, et al. Modulation of 5-fluorouracil toxicity by allopurinol in man. Cancer 48: 1281–1289, 1981

    Article  PubMed  CAS  Google Scholar 

  • Ikenaka K, Shirasaka T, Kitano S, Fujii S. Effect of uracil on metabolism of 5-fluorouracil in vitro. Gann 70: 353–359, 1979

    PubMed  CAS  Google Scholar 

  • Ingraham HA, Tseng BY, Goulian M. Mechanism for exclusion of 5-fluorouracil from DNA. Cancer Research 40: 998–1001, 1980

    PubMed  CAS  Google Scholar 

  • Ingraham HA, Tseng BY, Goulian M. Nucleotide levels and incorporation of 5-fluorouracil and uracil into DNA of cells treated with 5-fluorodeoxyuridine. Molecular Pharmacology 21: 211–216, 1982

    PubMed  CAS  Google Scholar 

  • Jacquez JA. Permeability of Ehrlich cells to uracil, thymine, and fluorouracil. Proceedings of the Society of Experimental Biology and Medicine 109: 132–135, 1962

    CAS  Google Scholar 

  • Kemeny MM, Goldberg DA, Browning S, Metter GE, Miner PJ, et al. Experience with continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. Cancer 55: 1265–1270, 1985

    Article  PubMed  CAS  Google Scholar 

  • Kessel D. Cell surface alterations associated with exposure of leukemia L1210 cells to fluorouracil. Cancer Research 40: 322–324, 1980

    PubMed  CAS  Google Scholar 

  • Kessel D, Hall TC. Studies on drug transport by normal human leukocytes. Biochemical Pharmacology 16: 2395–2403, 1967

    Article  PubMed  CAS  Google Scholar 

  • Kessel D, Hall TC, Wodinsky I. Nucleotide formation as a determinant of 5-fluorouracil response in mouse leukemias. Science 154: 911–913, 1966

    PubMed  CAS  Google Scholar 

  • Kufe DW, Major PP, Egan EM, Loh E. 5-Fluoro-2′-deoxyuridine incorporation in L1210 DNA. Journal of Biological Chemistry 256: 8885–8888, 1981

    PubMed  CAS  Google Scholar 

  • Kufe DW, Scott P, Fram R, Major P. Biological effect of 5-fluoro-2′-deoxyuridine incorporation in L1210 deoxyribonucleic acid. Biochemical Pharmacology 32: 1337–1340, 1983

    Article  PubMed  CAS  Google Scholar 

  • Lakings DB, Adamson RH, Diasio RB. Quantitative analysis of 5-fluorouracil in human serum by selected ion monitoring gas chromatography-mass spectrometry. Journal of Chromatography — Biomedical Applications 146: 512–517, 1978

    Article  PubMed  CAS  Google Scholar 

  • Liebecq C, Peters RA. The toxicity of fluoroacetate and the tricarboxylic acid cycle. Biochimica Biophysica Acta 3: 215–230, 1949

    Article  CAS  Google Scholar 

  • Lindahl T. DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision repair. In Cohen WE (Ed.) Progress in nucleic acid research molecular biology, Vol. 22, pp. 135–192, Academic Press, New York, 1979

    Google Scholar 

  • Lindahl T, Ljunquist S, Siegert N, Nyberg B, Sperens B. DNA N-glycosidases: Properties of uracil-DNA glycosidase from Escherichia coli. Journal of Biological Chemistry 252: 3286–3294, 1977

    PubMed  CAS  Google Scholar 

  • Lokich J, Fine N, Perri J, Bothe A. Protracted ambulatory venous infusion of 5-fluorouracil. American Journal of Clinical Oncology Cancer Clinical Trials 6: 103–107, 1983

    CAS  Google Scholar 

  • Lonn U, Lonn S. Interaction between 5-fluorouracil and DNA of human colon adenocarcinoma. Cancer Research 44: 3414–3418, 1984

    PubMed  CAS  Google Scholar 

  • Lonn U, Lonn S. DNA lesions in human neoplastic cells and cytotoxicity of 5-fluoropyrimidines. Cancer Research 46: 3866–3870, 1986

    PubMed  CAS  Google Scholar 

  • Lozeron HA, Gordon MP, Gabriel T, Tautz W, Duschinsky R. The photochemistry of 5-fluorouracil. Biochemistry 3: 1844–1850, 1964

    Article  PubMed  CAS  Google Scholar 

  • MacMillan WE, Wolberg WH, Welling PG. Pharmacokinetics of 5-fluorouracil in humans. Cancer Research 38: 3479–3482, 1978

    PubMed  CAS  Google Scholar 

  • Maguire JH, Dudley KH. Partial purification and characterization of dihydropyrimidinase from calf and rat liver. Drug Metabolism and Disposition 6: 601–610, 1978

    PubMed  CAS  Google Scholar 

  • Major PP, Egan E, Herrick D, Kufe DW. 5-Fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Research 42: 3005–3009, 1982

    PubMed  CAS  Google Scholar 

  • Mandel HG. The incorporation of 5-fluorouracil into RNA and its molecular consequences. Progress in Molecular and Subcellular Biology 1: 82–135, 1969

    Article  CAS  Google Scholar 

  • Martin DS, Nayak P, Sawyer RC, Stolfi RL, Young CW, et al. Enhancement of 5-fluorouracil chemotherapy with emphasis on the use of excess thymidine. Cancer Bulletin 30: 219–224, 1978

    Google Scholar 

  • McDermott BJ, Van den Berg HW, Martin WMC, Murphy RF. Pharmacokinetic rationale for the interaction of 5-fluorouracil and misonidazole in humans. British Journal of Cancer 48: 705–710, 1983

    Article  PubMed  CAS  Google Scholar 

  • McDermott BJ, Van den Berg HW, Murphy RF. Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. Cancer Chemotherapy and Pharmacology 9: 173–178, 1982

    Article  PubMed  CAS  Google Scholar 

  • McNally NJ. Enhancement of chemotherapy agents. International Journal of Radiation Oncology Biology & Physics 8: 593–598, 1982

    Article  CAS  Google Scholar 

  • Mentre F, Steimer JL, Sommadossi JP, Diasio RB, Cano JP. A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes. Biochemical Pharmacology 33: 2727–2732, 1984

    Article  PubMed  CAS  Google Scholar 

  • Millar BC. Hypoxic cell radiosensitizers as potential adjuvants to conventional chemotherapy for the treatment of cancer. Biochemical Pharmacology 31: 2439–2445, 1982

    Article  PubMed  CAS  Google Scholar 

  • Moran RG, Spears CPO, Heidelberger C. Biochemical determinants to tumor sensitivity to 5-fluorouracil: ultrasensitive methods for the determination of 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate, and thymidylate synthetase. Proceedings of the National Academy of Science 76: 1456–1460, 1979

    Article  CAS  Google Scholar 

  • Mukherjee KL, Boohar J, Wentland D, Ansfield FJ, Heidelberger C. Studies on fluorinated pyrimidines. XVI. Metabolism of 5-fluorouracil-2-14C and 5-fluoro-2′-deoxyuridine-2-14C in cancer patients. Cancer Research 23: 49–66, 1965

    Google Scholar 

  • Mukherjee KL, Heidelberger C. Studies on fluorinated pyrimidines. IX. The degradation of 5-fluorouracil-6-C14. Journal of Biological Chemistry 235: 433–437, 1960

    PubMed  CAS  Google Scholar 

  • Mulder JH, Smink T, van Putten LM. 5-Fluorouracil and methotrexate combination chemotherapy: the effect of drug scheduling. European Journal of Cancer and Clinical Oncology 17: 831–837, 1981

    Article  CAS  Google Scholar 

  • Myers CE. The pharmacology of the fluoropyrimidines. Pharmacological Reviews 33: 1–15, 1981

    PubMed  CAS  Google Scholar 

  • Myers CE. The use of intraperitoneal chemotherapy in the treatment of ovarian cancer. Seminars in Oncology 11: 275–284, 1984

    PubMed  CAS  Google Scholar 

  • Myers CE, Young RC, Chabner BA. Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion. Journal of Clinical Investigation 56: 1231–1238, 1975

    Article  PubMed  CAS  Google Scholar 

  • Naguib FMN, el Kouni MH, Cha S. Enzymes of uracil catabolism in normal and neoplastic human tissue. Cancer Research 45: 5404–5412, 1985

    Google Scholar 

  • Parker WB, Kennedy KA, Klubes P. Dissociation of 5-fluorouracil into DNA and its cytotoxicity in murine T-lymphoma (S-49) cells. Cancer Research 47: 979–982, 1987

    PubMed  CAS  Google Scholar 

  • Petit E, Milano G, Levi F, et al. Circadian rhythm-varying plasma concentration of 5-fluorouracil during a five-day continuous venous infusion at a constant rate in cancer patients. Cancer Research 48: 1676–1679, 1988

    PubMed  CAS  Google Scholar 

  • Petrelli N, Stablein D, Bruckner H, et al. A prospective randomized phase III trial of 5-fluorouracil (5FU) versus 5FU + high dose leucovorin (HDCF) versus 5FU + low dose leucovorin (LDCF) in patients (PTS) with metastatic colorectal adenocarcinoma. Proceedings of the American Society of Clinical Oncology 7: 94, 1988

    Google Scholar 

  • Powis G. Effect of human renal and hepatic disease on the pharmacokinetics of anticancer drugs. Cancer Treatment Reviews 9: 85–124, 1982

    Article  PubMed  CAS  Google Scholar 

  • Ramberg ES, Ishaq M, Rulf S, Moeller B, Horowitz J. Inhibition of transfer RNA function by replacement of uridine and uridine-derived nucleosides with 5-fluorouridine. Biochemistry 17: 3978–3985, 1978

    Article  PubMed  CAS  Google Scholar 

  • Riechard P, Skold O, Klein G. Possible enzymic mechanism for the development of resistance against fluorouracil in ascites tumors. Nature 183: 939–941, 1959

    Article  Google Scholar 

  • Reichard P, Skold O, Klein G, Revesz L, Magnusson P-H. Studies on resistance against fluorouracil. I. Enzymes of the uracil pathway during development of resistance. Cancer Research 22: 235–243, 1962

    PubMed  CAS  Google Scholar 

  • Robins MJ, Naik SR. Nucleic acid related compounds III. A facile synthesis of 5-fluorouracil bases and nucleosides by direct fluorination. Journal of the American Chemical Society 93: 5277–5278, 1971

    Article  PubMed  CAS  Google Scholar 

  • Roemeling RV, Hrushesky WJM. Circadian pattern of continuous FUDR infusion reduces toxicities. Progress in Clinical and Biological Research 227B: 357–373, 1987

    PubMed  CAS  Google Scholar 

  • Rutman RJ, Cantarow A, Paschkis KE. Studies in 2-acetylaminofluorene carcinogenesis III. The utilization of uracil-2-14C by preneoplastic rat liver and rat hepatoma. Cancer Research 14: 119–134, 1954

    PubMed  CAS  Google Scholar 

  • Sanno Y, Holzer M, Schimple RT. Studies of a mutation affecting pyrimidine degradation in inbred mice. Journal of Biological Chemistry 245: 5658–5676, 1970

    Google Scholar 

  • Santi DV, McHenry CS. 5-Fluoro-2′-deoxyuridylate: covalent complex with thymidylate synthetase. Proceedings of the National Academy of Sciences, USA 69: 1855–1857, 1972

    Article  CAS  Google Scholar 

  • Santi DV, McHenry CS, Sommer H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13: 471–481, 1974

    Article  PubMed  CAS  Google Scholar 

  • Schaaf LJ, Dobbs BR, Edwards IR, Perrier DG. Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients. European Journal of Clinical Pharmacology 32: 411–418, 1987

    Article  PubMed  CAS  Google Scholar 

  • Schuetz JD, Collins JM, Wallace HJ, Diasio RB. Alteration of the secondary structure of newly synthesized DNA from murine bone marrow cells by 5-fluorouracil. Cancer Research 46: 119–123, 1986

    Article  PubMed  CAS  Google Scholar 

  • Schuetz JD, Diasio RB. The effect of 5-fluorouracil on DNA chain elongation in intact bone marrow cells. Biochemical and Biophysical Research Communications 133: 361–367, 1985

    Article  PubMed  CAS  Google Scholar 

  • Schuetz JD, Wallace HJ, Diasio RB. 5-Fluorouracil incorporation into DNA of CF-1 mouse bone marrow cells as a possible mechanism of toxicity. Cancer Research 44: 1358–1363, 1984

    PubMed  CAS  Google Scholar 

  • Schuetz JD, Wallace HJ, Diasio RB. DNA repair following incorporation of 5-fluorouracil into DNA of mouse bone marrow cells. Cancer Chemotherapy and Pharmacology 21: 208–210, 1988

    Article  PubMed  CAS  Google Scholar 

  • Shiotani T, Weber G. Purification and properties of dihydrothymine dehydrogenase from rat liver. Journal of Biological Chemistry 256: 219–224, 1981

    PubMed  CAS  Google Scholar 

  • Sitar DS, Shaw DHJ, Thirwell MP, Ruedy JR. Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation to cancer patients. Cancer Research 37: 3981–3984, 1977

    PubMed  CAS  Google Scholar 

  • Skold O. Studies on resistance against 5-fluorouracil. IV. Evidence for an altered uridine kinase in resistant cells. Biochimica et Biophysica Acta 76: 160–162, 1963

    Article  CAS  Google Scholar 

  • Sommadossi JP, Cross DS, Gewirtz DA, Goldman ID, Diasio RB. Evidence from rat hepatocytes of an unrecognized pathway of 5-fluorouracil metabolism with the formation of a glucuronide derivative. Cancer Research 45: 2450–2455, 1985a

    PubMed  CAS  Google Scholar 

  • Sommadossi JP, Gewirtz DA, Cross DS, Goldman ID, Diasio RB. Modulation of 5-fluorouracil catabolism in freshly isolated rat hepatocytes by thymine or uracil: therapeutic implications. Cancer Research 45: 116–121, 1985b

    PubMed  CAS  Google Scholar 

  • Sommadossi JP, Gewirtz DA, Diasio RB, Aubert C, Cano JP, et al. Rapid catabolism of 5-fluorouracil in freshly isolated rat hepatocytes as analyzed by high performance liquid chromatography. Journal of Biological Chemistry 357: 8171–8176, 1982

    Google Scholar 

  • Spears CP, Gustavsson BG. Methods for thymidylate synthase pharmacodynamics: serial biopsy, free and total TS, FdUMP and dUMP, and H4PteGlu and CH2-H4PteGlu assays. In Rustum et al. (Eds) The expanding role of folates and fluoropyrimidines in cancer chemotherapy. Plenum Press, New York, 1988

    Google Scholar 

  • Spears CP, Gustavsson BG, Berne M, Frosing R, Hayes AA. Mechanisms of innate resistance to thymidylate synthase inhibition after 5-fluorouracil. Cancer Research, in press, 1988a

    Google Scholar 

  • Spears CP, Gustavsson BG, Karlsson G, Frosing R. Fluorouracil/leucovorin pharmacodynamics: determination by serial biopsy. Proceedings of the American Association for Cancer Research 29: 186, 1988b

    Google Scholar 

  • Spicer DV, Ardalan B, Daniels JB, Silbermann H, Johnson K. Reevaluation of the maximum tolerated dose of continuous venous infusion of 5-fluorouracil with pharmacokinetics. Cancer Research 48: 459–461, 1988

    PubMed  CAS  Google Scholar 

  • Spooner D, Bugden RD, Peckham MJ, Wist EA. The combination of 5-fluorouracil with misonidazole in patients with advanced colorectal cancer. International Journal of Radiation Oncology Biology and Physics 8: 387–389, 1982

    Article  CAS  Google Scholar 

  • Stoll HL. Topical chemotherapy. In Helm F (Ed.) Cancer dermatology, pp. 435–448, Lea & Febiger, Philadelphia, 1979

    Google Scholar 

  • Sweeny DJ, Barnes S, Diasio RB. Production of cholestasis by 2-fluoro-β-alanine-chenodeoxycholic acid: possible role of this metabolite in the cholestasis associated with hepatic arterial infusion of fluoropyrimidines. Proceedings of the American Association for Cancer Research 29: 486, 1988a

    Google Scholar 

  • Sweeny DJ, Barnes S, Heggie GD, Diasio RB. Metabolism of 5-fluorouracil to a N-cholyl-2-fluoro-β-alanine conjugate: a novel role for bile acids in drug conjugation. Proceedings of the National Academy of Sciences, USA 84: 5439–5443, 1987

    Article  CAS  Google Scholar 

  • Sweeny DJ, Martin M, Diasio RB. N-chenodeoxycholyl-2-fluoro-β-alanine: a biliary metabolite of 5-fluorouracil in man. Drug Metabolism and Disposition 16: 892–894, 1988b

    PubMed  CAS  Google Scholar 

  • Tanaka M, Yoshida S, Saneyoshi M, Yamaguchi T. Utilization of 5-fluoro-2′-deoxyuridine triphosphate and 5-fluoro-2′-deoxycytidine triphosphate in DNA synthesis by DNA polymerase α and β from calf thymus. Cancer Research 41: 4132–4135, 1981

    PubMed  CAS  Google Scholar 

  • Tattersall MHN, Jackson RG, Connors TA, Harrap KR. Combination chemotherapy: The interaction of methotrexate and 5-fluorouracil. European Journal of Cancer 9: 733–739, 1973

    Article  PubMed  CAS  Google Scholar 

  • Tuchman M, Roemeling RV, Lanning RM, Sothern RB, Hrushesky WJM. Sources of variability of dihydropyrimidine dehydrogenase activity in human blood mononuclear cells. Annual Review of Chronopharmacology, in press, 1988

    Google Scholar 

  • Ullman B, Lee M, Martin DW Jr, et al. Cytotoxicity of 5-fluoro-2′-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proceedings of the National Academy of Sciences, USA 75: 980–983, 1978

    Article  CAS  Google Scholar 

  • Vessey DA. The co-purification and common identity of cholyl CoA:glycine- and CoA:taurine-n-acyltransferase activities from bovine liver. Journal of Biological Chemistry 254: 2059–2063, 1979

    PubMed  CAS  Google Scholar 

  • Walliser S, Redmann K. Effect of 5-fluorouracil and thymidine on the transmembrane potential and zeta potential of HeLa cells. Cancer Research 38: 3555–3559, 1978

    PubMed  CAS  Google Scholar 

  • Wasternak C. Degradation of pyrimidines and pyrimidine analogs — pathways and mutual influences. Pharmacology Therapeutics 8: 629–651, 1980

    Article  Google Scholar 

  • Wohlhueter RM, McIvar RS, Plageman PGW. Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells. Journal of Cellular Physiology 104: 309–319, 1980

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Robert B. Diasio & Barry E. Harris

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Diasio, R.B., Harris, B.E. Clinical Pharmacology of 5-Fluorouracil. Clin-Pharmacokinet 16, 215–237 (1989). https://doi.org/10.2165/00003088-198916040-00002

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