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Part of the book series: Cancer Treatment and Research ((CTAR,volume 78))

Abstract

Antimetabolites are a class of chemotherapeutic agents that have a chemical structure similar to physiologic intermediates and can function as substrates for important enzymatic reactions required in vital cell biologic processes, e.g., synthesis of DNA and RNA. Several reviews on the metabolism of antimetabolite drugs have recently been published, providing a general background on these drugs [1–5]. The pyrimidine antimetabolite drugs consist of base or nucleoside analogues of the naturally occurring pyrimidines, i.e., uracil, thymine, and cytosine. They have a strong structural similarity to these endogenous nucleic acid precursors, with structural differences including substitutions at one of the carbons in the pyrimidine ring or one of the hydrogens attached to the ring of the pyrimidine or sugar (ribose or deoxyribose).

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References

  1. Allegra CJ, Grem JL, Chu E, Johnson P, Yeh GC, Chabner BA. Antimetabolites. Cancer Chemother Biol Response Modif 11:1–28, 1990.

    PubMed  CAS  Google Scholar 

  2. Daher GC, Harris BE, Diasio RB. Metabolism of pyrimidine analogues and their nucleosides. Pharmacol Ther 48:189–222, 1990.

    Article  PubMed  CAS  Google Scholar 

  3. Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther 48:381–395, 1990.

    Article  PubMed  CAS  Google Scholar 

  4. Weckbecker G. Biochemical pharmacology and analysis of fluoropyrimidines alone and in combination with modulators. Pharmacol Ther 50:367–424, 1991.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang R, Diasio RB. Pharmacologic basis for circadian pharmacodynamics. In Hrushesky WJM (ed), Circadian Cancer Therapy. CRC: Boca Raton, FL, 1994, pp 61–103.

    Google Scholar 

  6. Ensminger WD, Rosowsky A, Vic R, Levin DC, Glode M, Come S, Steele G, Frei E. A clinical-pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2’-deoxyuridine and 5-fluorouracil. Cancer Res 38:3784–3792, 1978.

    PubMed  CAS  Google Scholar 

  7. Chabner BA. Pyrimidines antagonists. In Chabner BA (ed), Pharmacologie Principles of Cancer Treatment. W.B. Saunder: Philadelphia, 1982, pp 183–212.

    Google Scholar 

  8. Chabner BA, Myers CE. Clinical pharmacology of cancer chemotherapy. In De Vita VT, Hellman S, Rosenberg SA (eds), Cancer — Principles and Practice of Oncology. J.B. Lippincott: Philadelphia, 1989, pp 349–395.

    Google Scholar 

  9. Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Ann Intern Med 107:459–465, 1987.

    PubMed  CAS  Google Scholar 

  10. Kemeny N, Sugarbaker PH. Treatment of metastatic cancer to liver. In Devita VT, Hellman S, Rosenberg SA (eds), Cancer — Principles and Practice of Oncology. J.B. Lippincott: Philadelphia, 1987, pp 2275–2298.

    Google Scholar 

  11. Saltz L. Drug treatment of colorectal cancer, current status. Drugs 42:616–627, 1991.

    Article  PubMed  CAS  Google Scholar 

  12. Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB. Clinical pharmacokinetics of 5-fluorouracil and its metabolities in plasma, urine, and bile. Cancer Res 47:2203–2206, 1987.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  14. Harris BE, Song R, Soong S-J, Diasio RB. Relationship between dihydropyrimidine 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, 1990.

    PubMed  CAS  Google Scholar 

  15. Fleming RA, Milano G, Thyss A, Etienne M-C, 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, 1992.

    PubMed  CAS  Google Scholar 

  16. Reyes P. The synthesis of 5-fluorouridine 5’-phosphate by a pyrimidine phosphorbosyl-transferase of mammalian origin. I. Some properties of the enzyme from P1534J mouse leukemic cells. Biochemistry 8:2057–2062, 1969.

    Article  PubMed  CAS  Google Scholar 

  17. Sköld O. Enzymic ribosidation and ribotidation of 5-fluorouracil by extracts of the Ehrlich-ascites tumor. Biochim Biophys Acta 29:651, 1958.

    Article  PubMed  Google Scholar 

  18. Hartmann KV, Heidelberger C. Studies on fluorinated pyrimidines XIII. Inhibition of thymidylate synthetase. J Biol Chem 236:3006–3013, 1961.

    PubMed  CAS  Google Scholar 

  19. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215–237, 1989.

    Article  PubMed  CAS  Google Scholar 

  20. Naguib FNM, el Kouni MH, Cha S. Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 45:5405–5412, 1985.

    PubMed  CAS  Google Scholar 

  21. Lu Z, Zhang R, Diasio RB. Purification and characterization of dihydropyrimidine dehydrogenase from human liver. J Biol Chem 267:17102–17109, 1992.

    PubMed  CAS  Google Scholar 

  22. Lu Z, Zhang R, Diasio RB. Comparison of dihydropyrimidine dehydrogenase from human, rat pig, and cow liver. Biochem Pharmacol 46:945–952, 1993.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang R, Soong S-J, Liu T, Barnes S, Diasio RB. Pharmacokinetics and tissue distribution of 2-fluoro-β-alanine: possible relevance to toxicity pattern of 5-fluorouracil. Drug Metab Disp 20:113–119, 1992.

    CAS  Google Scholar 

  24. Wallach DP, Santiago G. The purification and properties of hydropyrimidine hydrase. J Biol Chem 251:6909–6914, 1957.

    Google Scholar 

  25. Maguire JH, Dudley KH. Partial purification and characterization of dihydropyrimidinases from calf and rat liver. Drug Metab Disp 6:601–605, 1978.

    CAS  Google Scholar 

  26. Brooks KP, Jones EA, Kim BD, Sander EG. Bovine liver dihydropyrimidine amidohydrolase: purification, properties, and characterization as a zinc metalloenzyme. Arch Biochem Biophys 226:469–483, 1983.

    Article  PubMed  CAS  Google Scholar 

  27. Lee MH, Cowling RA, Sander EG, Pettigrew DW. Bovine liver dihydropyrimidine amidohydrolase: pH dependencies of inactivation by chelators and steady state kinetic properties. Arch Biochem Biophys 248:368–378, 1986.

    Article  PubMed  CAS  Google Scholar 

  28. Duran M et al. Dihydropyrimidinuria. Lancet 336:817–818, 1990.

    Article  PubMed  CAS  Google Scholar 

  29. Duran M, Rovers P, De Bree PK. Dihydropyrimidinuria: a new inborn error of pyrimidine metabolism. J Inher Metab Dis 14:367–370, 1991.

    Article  PubMed  CAS  Google Scholar 

  30. Tamaki N, Mizutani N, Kikugawa M, Fujimoto S, Mizota C. Purification and properties of β-ureidopropionase from the rat liver. Eur J Biochem 169:21–26, 1987.

    Article  PubMed  CAS  Google Scholar 

  31. Matthews MM, Traut TW. Regulation of N-carbamoyl-β-alanine amidohydrolase, the terminal enzyme in pyrimidine catabolism, by ligand-induced change in polymerization. J Biol Chem 262:7232–7237, 1987.

    PubMed  CAS  Google Scholar 

  32. Sweeny DJ, Barnes S, Heggie GH, Diasio RB. Metabolism of 5-fluorouracil to an N-cholyl-2-fluoro-β-alanine conjugate: Previously unrecognized role for bile acids in drug conjugation. Proc Natl Acad Sci USA 84:5439–5443, 1987.

    Article  PubMed  CAS  Google Scholar 

  33. Sweeny DJ, Barnes S, Diasio RB. Formation of conjugates of 2-fluoro-β-alanine and bile acids during the metabolism of 5-fluorouracil and 5-fluoro-2-deoxyuridine in the isolated perfused rat liver. Cancer Res 48:2010–2014, 1988.

    PubMed  CAS  Google Scholar 

  34. Johnson MJ, Barnes S, Kwakye JB, Diasio RB. Purification and characterization of bile acid-CoA: amino acid: N-acyltransferase from human liver. J Biol Chem 266: 10227–10233, 1991.

    PubMed  CAS  Google Scholar 

  35. Falany CN, Johnson MJ, Barnes S, Diasio RB. Glycine and taurine conjugation of bile acids by a single enzyme. Molecular cloning and expression of human liver bile acid-CoA: amino acid: N-acyltransferase. J Biol Chem, in press.

    Google Scholar 

  36. Zhang R, Barnes S, Diasio RB. Disposition and metabolism of 2-fluoro-β-alanine conjugates of bile acids following secretion into bile. Biochim Biophys Acta 1096:179–186, 1991.

    Article  PubMed  CAS  Google Scholar 

  37. Grisolia S, Cardoso SS. The purification and properties of hydropyrimidine dehydrogenase. Biochim Biophys Acta 25:430–431, 1957.

    Article  PubMed  CAS  Google Scholar 

  38. Porter DJT, Chestnut WG, Taylor LCE, Merrill BM, Spector T. Inactivation of dihydropyrimidine dehydrogenase by 5-iodouracil. J Biol Chem 266:19988–19994, 1991.

    PubMed  CAS  Google Scholar 

  39. Fritzson P. Properties and assay of dihydrouracil dehydrogenase of rat liver. J Biol Chem 235:719–725, 1960.

    PubMed  CAS  Google Scholar 

  40. Shiotani T, Weber G. Purification and properties of dihydrothymine dehydrogenase from rat liver. J Biol Chem 256:219–224, 1981.

    PubMed  CAS  Google Scholar 

  41. Fujimoto S, Matsuda K, Kikugama M, Kaneko M, Tamak N. Effect of vitamin B2 deficiency on rat liver dihydropyrimidine dehydrogenase activity. J Nutr Sci Vitaminol 37:89–98, 1990.

    Article  Google Scholar 

  42. Sanno Y, Holzer M, Schimke RT. Studies of a mutation affecting pyrimidine degradation in inbred mice. J Biol Chem 245:5668–5676, 1970.

    PubMed  CAS  Google Scholar 

  43. Goedde HW, Agarwal DP, Eickhoff K. Purification and properties of dihydrouracil dehydrogenase from pig liver. Hoppe-Seyler’s Z Physiol Chem 351:945–951, 1970.

    Article  PubMed  CAS  Google Scholar 

  44. Podschun B, Wahler G, Schnackerz KD. Purification of dihydropyrimidine dehydrogenase from pig liver. Eur J Biochem 185:219–224, 1989.

    Article  PubMed  CAS  Google Scholar 

  45. Cheng X, Zhang R, Lu Z, Falany CN, Diasio RB. Molecular cloning of dihydropyrimidine dehydrogenase (DPD): Isolation of cDNA fragments of bovine liver. Clin Pharmacol and Ther 54:188, 1994.

    Google Scholar 

  46. Iigo M, Nishikata K, Nakajima Y, Hoshi A, Okudaiera N, Odagiri H, De Clereq E. Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5’-deoxy-5-fluorouridine against adenocarcinoma 755 in mice. Correlation with pharmacokinetics of plasma 5-fluorouracil levels. Biochem Pharmacol 38:1885–1889, 1989.

    Article  PubMed  CAS  Google Scholar 

  47. Martin DS, Nayak P, Sawyer RC, Stolfl RL, Young CW, Woodcock T, Spiegelman S. Enhancement of 5-fluorouracil chemotherapy with emphasis on the use of excess thymidine. Cancer Bulletin 30:219–224, 1978.

    Google Scholar 

  48. Wasternack C. Degradation of pyrimidines and pyrimidine analogs — pathways and mutual influences. Pharmacol Ther 8:629–665, 1980.

    Article  PubMed  CAS  Google Scholar 

  49. Daher GC, Naguib FNM, el Kouni MH, Zhang R, Soong S-J, Diasio RB. Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil. Possible relevance to regional chemotherapy. Biochem Pharmacol 41:1887–1893, 1991.

    Article  PubMed  CAS  Google Scholar 

  50. Porter DJT, Chestnut WG, Merrill BM, Spector T. Mechanism based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 267:5236–5242, 1992.

    PubMed  CAS  Google Scholar 

  51. Spector T, Porter DJT, Nelson DJ, Baccanari DP, Davis ST, Almond, MR, Khor SP, Amyx H, Cao S, Rustum YM. 5-Ethynyluracil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drug of the Future, in press.

    Google Scholar 

  52. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. J Clin Invest 81:47–51, 1988.

    Article  PubMed  CAS  Google Scholar 

  53. Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency: a potentially more common pharmacogenetic syndrome. Cancer 68:499–501, 1991.

    Article  PubMed  CAS  Google Scholar 

  54. Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 53:5433–5438, 1993.

    PubMed  CAS  Google Scholar 

  55. Sommadossi J-P, Gewirtz DA, Diasio RB, Aubert C, Cano JP, Goldman ID. Rapid catabolism of 5-fluorouracil in freshly isolated hepatocytes as analyzed by high performance liquid chromatography. J Biol Chem 257:8171–8176, 1982.

    PubMed  CAS  Google Scholar 

  56. Lu Z, Zhang R, Diasio RB. Genetic polymorphism of dihydropyrimidine dehydrogenase (DPD), the key enzyme in 5-fluorouracil (FUra) catabolism. Clin Pharmacol and Ther 54:180, 1994.

    Google Scholar 

  57. Zhang R, Lu Z, Diasio RB. Quantitation of dihydropyrimidine dehydrogenase (DPD) using a polyclonal antibody to human liver DPD. Proc Am Assoc Cancer Res 35:200, 1994.

    Google Scholar 

  58. Diasio RB, Van Kuilenburg ABP, Lu Z, Zhang R, Van Lenthe H, Bakker HD, Van Gennip AH. Determination of dihydropyrimidine dehydrogenase (DPD) in fibroblasts of a DPD deficient pediatrie patient and family members using a polycolonal antibody to human DPD. The 8th Int Symp Purine Pyrimidin, in press.

    Google Scholar 

  59. Tuchman M, Stoeckeler JS, Kiang DT, O’Dea RF, Rammaraine ML, Mirkin BL. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med 313:245–249, 1985.

    Article  PubMed  CAS  Google Scholar 

  60. Lyss AP, Lilenbaum RC, Harries BE, Diasio RB. Severe 5-fluorouracil toxicity in a patient with decreased dihydropyrimidine dehydrogenase activity. Cancer Invest 11: 239–240, 1993.

    Article  PubMed  CAS  Google Scholar 

  61. 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:740–744, 1993.

    PubMed  CAS  Google Scholar 

  62. Houyan P, Gay C, Chatelut E, Canal P, Milano G. Severe fluorouracil toxicity in a patient with dihydropyrimidine dehydrogenase deficiency. J Natl Cancer Inst 85: 1602–1603, 1993.

    Article  Google Scholar 

  63. Wadman SK, Beemer FA, de Bree PK, Duran M, van Gennip AH, Ketting D, van Sprang FJ. New defects of pyrimidine metabolism. Adv Exp Med Biol 165A:109–114, 1984.

    Article  Google Scholar 

  64. Bakkeren JAJM, de Abreu RA, Sengers RCA, Gabreels FJM, Maas JM, Renier WO. Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta 140:247–256, 1984.

    Article  PubMed  CAS  Google Scholar 

  65. Berger R, Stokerde Vries SA, Wadman SK, Duran M, Beemer FA, deBree PK, Weits-Binnerts JJ. Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. Clin Chim Acta 141:227–234, 1984.

    Article  PubMed  CAS  Google Scholar 

  66. Meyer UA, Zanger UM, Skoda RC, Grant D, Blum M. Genetic polymorphisms of drug metabolism. Prog Liver Dis 9:307–323, 1990.

    PubMed  CAS  Google Scholar 

  67. Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Saantini J, Frenay M, Renee N, Schneider M, Demard F. Influence of sex and age on fluorouracil clearance. J Clin Oncol 10:1171–1175, 1992.

    PubMed  CAS  Google Scholar 

  68. Lu Z, Zhang R, Carpenter J, Diasio RB. Frequency of dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients. Proc Am Assoc Cancer Res 35:227, 1994.

    Google Scholar 

  69. Ho DH, Townsend L, Luma MA, Bodely GP. Distribution and inhibition of dihydrouracil dehydrogenae activities in human tissues using 5-fluorouracil as a substrate. Anticancer Res 6:781–784, 1986.

    PubMed  CAS  Google Scholar 

  70. Popovic P, Popovic V, Bauhman. Circadian rhythm and 5-fluorouracil toxicity in C3H mice. Biomed Therm 25:185–187, 1982.

    Google Scholar 

  71. Burns ER, Beland SS. Effect of biological time on the determination of the LD50 of 5-fluorouracil in mice. Pharmacology 28:296–300, 1984.

    Article  PubMed  CAS  Google Scholar 

  72. Peters GJ, Van Dijk J, Nadal JC, Van Groeningen CJ, Lankelma J, Pinedo HM. Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer. In Vivo 1:113–118, 1987.

    PubMed  CAS  Google Scholar 

  73. Hrushesky WJM, von Roemeling R, Fraley EE, Rabatin JT. Circadian-based infusional chrono-chemotherapy controls progressive metastatic renal cell carcinoma. Semin Surg Oncol 4:110–115, 1988.

    PubMed  CAS  Google Scholar 

  74. Hrushesky WJM, von Roemeling R, Wood PA, Langevin TR, Lange P, Farley E. High-dose intensity systemic therapy of metastatic bladder cancer. J Clin Oncol 5:450–455, 1987.

    PubMed  CAS  Google Scholar 

  75. Dexeus FH, Logothetis CJ, Sella A, Amato R, Kilbourn R, Ogden S, Striegel A, Kwan J, Newman RA. Circadian infusion of floxuridine in patients with metastatic renal cell carinoma. J Urol 146:709–713, 1991.

    PubMed  CAS  Google Scholar 

  76. von Roemeling R, Hrushesky WJM. Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer. J Clin Oncol 7:1710–1719, 1989.

    Google Scholar 

  77. von Roemeling R, Hrushesky WJM. Determination of the therapeutic index of floxuridine by its circadian infusion pattern. J Natl Cancer Inst 82:386–393, 1990.

    Article  Google Scholar 

  78. Damascelli B, Marchiano A, Frigerio LF, Salvetti M, Spreafico C, Garbagnati F, Zanoni F, Radice F. Flexibility and efficacy of automatic continuous fluorodeoxyuridine infusion in metastases from a renal cell carcinoma. Cancer 68:995–998, 1991.

    Article  PubMed  CAS  Google Scholar 

  79. Levi F, Misset J-L, Brienza S, Adam R, Metzger G, Itzakhi M, Caussanel J-P, Kunstlinger F, Lecouturier S, Descorps-Declere A, Jasmin C, Bismuth H, Reinberg A. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxalipatin using an ambulatory multichannel programmable pump. Cancer 69:893–900, 1992.

    Article  PubMed  CAS  Google Scholar 

  80. el Kouni MH, Naguib FNM, Park KS, Cha S, Darnowsk JW, Soong SJ. Circadian rhythm of hepatic uridine phosphorylase activity and plasma concentration of uridine in mice. Biochem Pharmacol 40:2479–2485, 1990.

    Article  PubMed  Google Scholar 

  81. Harris BE, Song R, He Y-J, Soong S-J, Diasio RB. Orcadian rhythm of rat liver dihydropyrimidine dehydrogenase, possible relevance to fluoropyrimidine chemotherapy. Biochem Pharmacol 37:4759–4762, 1988.

    Article  PubMed  CAS  Google Scholar 

  82. Harris BE, Song R, Soong S-J, Diasio RB. Crcadian variation of 5-fluorouracil catabolism in isolated perfused rat liver. Cancer Res 49:6610–6614, 1989.

    PubMed  CAS  Google Scholar 

  83. Daher GC, Harris BE, Zhang R, Willard EM, Soong S-J, Diasio RB. The role of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (dThdPase) in the circadian variation of plasma drug levels of 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd) following infusion of FUra or FdUrd. Annu Rev Chronopharmacol 7:227–230, 1990.

    Google Scholar 

  84. Daher GC, Harris BE, Willard EM, Diasio RB. Biochemical basis for circadian-dependent metabolism of fluoropyrimidines. Ann N Y Acad Sci 618:350–361, 1991.

    Article  PubMed  Google Scholar 

  85. Daher GC, Zhang R, Soong S-J, Diasio RB. Circadian variation of fluoropyrimidine catabolic enzymes in rat liver: possible relevance to 5-fluorodeoxyuridine chemotherapy. Drug Metab Disp 19:285–287, 1991.

    CAS  Google Scholar 

  86. Zhang R, Lu Z, Liu T, Soong S-J, Diasio RB. Circadian rhythm of rat spleen cytoplasmic thymidine kinase. Biochem Pharmacol 45:1115–1119, 1993.

    Article  PubMed  CAS  Google Scholar 

  87. Zhang R, Lu Z, Liu T, Soong S-J, Diasio RB. Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes; possible relevance to fluoropyrimidine chemotherapy. Cancer Res 53:2816–2822, 1993.

    PubMed  CAS  Google Scholar 

  88. Naguib FNM, Soong S-J, el Kouni MH. Circadian rhythm of orotate phosphoribosyltrans-ferase, pyrimidine nucleoside phosphorylases and dihydrouracil dehydrogenase in mouse liver. Biochem Pharmacol 45:667–673, 1993.

    Article  PubMed  CAS  Google Scholar 

  89. Levi F, Zidani R, Di Palma M, Faggiuolo R, Garufi C, Chollet P, Focan C, Lacobelli S, Perpoint B, Le Rol A, Itzhaki M, Vannetzel JM, Misset JL. Improved therapeutic index through ambulatory circadian rhythmic delivery (CRD) of high dose 3-drug chemotherapy in a randomized phase III multicenter trial. Proc Am Soc Clin Oncol 13:197, 1994.

    Google Scholar 

  90. Kawai M, Rosenfeld J, McCulloch P, Hillcoat BL. Blood levels of 5-fluorouracil during intravenous infusion. Br J Cancer 36:346–347, 1976.

    Article  Google Scholar 

  91. Erlichman C, Fine S, Elhakim T. Plasma pharmacokinetics of 5-fluorouracil by continuous infusion with allopurinol. Cancer Treat Rep 70:903–904, 1986.

    PubMed  CAS  Google Scholar 

  92. 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 48:1676–1679, 1988.

    PubMed  CAS  Google Scholar 

  93. Smaaland R, Laerum OD, Lote K, Sletvold O, Sothern RB, Bjerknes R. DNA synthesis in human bone marrow is circadian stage dependent. Blood 77:2603–2611, 1991.

    PubMed  CAS  Google Scholar 

  94. Smaaland R, Svardal AM, Lote K, Ueland PM, Laerum OD. Glutathione content in human bone marrow and circadian stage relation to DNA synthesis. J Nat Cancer Inst 83:1092–1098, 1991.

    Article  PubMed  CAS  Google Scholar 

  95. Sletvold O, Smaaland R, Laerum OD. Cytometry and time-dependent variations in peripheral blood and bone marrow cells: a literature review and relevance to the chronotherapy of cancer. Chronobiol Int 8:235–250, 1991.

    Article  PubMed  CAS  Google Scholar 

  96. Buchi KN, Moore JG, Hrushesky WJM, Sothern RB, Rubin NH. Circadian rhythm of cellular proliferation in human rectal mucosa. Gastroenterology 101:410–415, 1991.

    PubMed  CAS  Google Scholar 

  97. Cooper GM, Dunning WF, Greer S. Role of catabolism in pyrimidine utilization for nucleic acid synthesis in vivo. Cancer Res 32:390–397, 1972.

    PubMed  CAS  Google Scholar 

  98. Desgranges C, Razaka G, De Clercq E, Herdewijn P, Balzarmi J, Drouillet F, Bricaud H. Effect of (E)-5-(2-bromovinyl)uracil on the catabolism and antitumor activity of 5-fluorouracil in rats and leukemic mice. Cancer Res 46:1094–1101, 1986.

    PubMed  CAS  Google Scholar 

  99. Matthews E, Barwolff D, Langen P. Inhibition by 6-aminothymine of the degradation of nucleosides (5-iododeoxyuridine, thymidine) and pyrimidine bases (5-iodouracil, uracil and 5-fluorouracil) in vivo. Acta Biol Med Germ 32:483–502, 1974.

    Google Scholar 

  100. Masaaki I, Araki E, Nakajima Y, De Clercq E. Enhancing effects of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels. Biochem Pharmacol 37:1609–1613, 1988.

    Article  Google Scholar 

  101. Naguib FNM, El Kouni MH, Cha S. Structure—activity relationship of ligands of dihydrouracil dehydrogenase from mouse liver. Biochem Pharmacol 38:1471–1480, 1989.

    Article  PubMed  CAS  Google Scholar 

  102. Iigo M, Araki E, Nakajima Y, Hoshi A, de Clercq E. Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenocarcinoma 755 in mice: increased therapeutic index and correlation with increased plasma 5-fluororacil level. Biochem Pharmacol 37:1609–1613, 1988.

    Article  PubMed  CAS  Google Scholar 

  103. Zhang R, Lu Z, Spector T, Diasio RB. Importance of dihydropyrimidine dehydrogenase (DPD) in circadian-dependent toxicity of 5-fluorodeoxyuridine: effect of 5-ethynyluracil, tan inhibitor of DPD. Biological Rhythms and Medications, Sixth International Conference of Chronopharmacology and Chronotherapeutics, pp VIII1–3.

    Google Scholar 

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Diasio, R.B., Lu, Z., Zhang, R., Shahinian, H.S. (1995). Fluoropyrimidine catabolism. In: Muggia, F.M. (eds) Concepts, Mechanisms, and New Targets for Chemotherapy. Cancer Treatment and Research, vol 78. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2007-8_4

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