Reduced folates and fluoropyrimidine antitumor efficacy

  • Janet A. Houghton
  • Peter J. Houghton
Part of the Cancer Treatment and Research book series (CTAR, volume 42)


During the last 30 years, the 5-fluoropyrimidines — 5-fluorouracil (FUra) and 5-fluoro-2′-deoxyuridine (FdUrd) — have become established as useful palliative agents in the treatment of certain malignancies in adults [1–3] and have been employed to a limited extent in children [4, 5]. They constitute some of the most extensively studied anticancer agents. However, the relevant mechanism(s) of action in human cancers in vivo achieved at pharmacologically tolerable dose levels remains the subject of considerable debate. For FUra, at least three mechanisms of cytotoxicity at the preclinical level have been proposed, each of which may be valid, dependent upon the model system used. It is because of this intense preclinical research into the metabolism of 5-fluoropyrimidines, and the interaction of metabolites with cellular macro-molecules, that various methods for modulating their potency, site of toxicity, and therapeutic utility have been proposed and tested both in model systems [6–10] and in clinical trials [11–14]. Our own interest in the concept of modulating 5-fluoropyrimidine action stems from studies in the late 1970s where attempts were made to elucidate mechanisms of intrinsic resistance to these agents, when human colon adenocarcinomas were heterografted into immune-deprived mice [15, 16].


Ternary Complex Human Colon Adenocarcinoma Ehrlich Ascites Tumor Cell Thymidylate Synthetase Metastatic Colorectal Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Moertel CG: Current concepts in cancer: chemotherapy of gastrointestinal cancer. N Engl J Med 299:1049–1052, 1978.PubMedCrossRefGoogle Scholar
  2. 2.
    Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. II. Large bowel carcinoma. Cancer Treat Rev 1:111–129, 1974.CrossRefGoogle Scholar
  3. 3.
    Carter SK: Single and combination nonhormonal chemotherapy in breast cancer. Cancer 30:1543–1555, 1972.PubMedCrossRefGoogle Scholar
  4. 4.
    Krivit W and Bently HP Jr: Use of 5-fluorouracil in the management of advanced malignancies in childhood. Am J Dis Child 100:87–97, 1960.Google Scholar
  5. 5.
    Haggard ME, Cangir A, Ragab AH, Komp D, Falleta J, and Humphrey GB: 5-Fluorouracil in childhood solid tumors. Cancer Treat Rep 61:69–71, 1977.PubMedGoogle Scholar
  6. 6.
    Burchenal JH, Oettgen HF, Reppert JA, and Coley V: Studies on the synergism of fluori-nated pyrimidines and certain pyrimidine and purine derivatives against transplanted mouse leukemia. Cancer Chem Rep 6:1–5, 1966.Google Scholar
  7. 7.
    Martin DS, Nayak R, Sawyer RC, et al.: Enhancement of 5-fluorouracil chemotherapy with emphasis on the use of excess thymidine. Cancer Bull 30:219–224, 1978.Google Scholar
  8. 8.
    Schwartz PM and Handschumacher RE: Selective antagonism of 5-fluorouracil cytotoxicity by 4-hydroxypyrazolopyrimidine (allopurinol) in vitro. Cancer Res 40:1885–1889, 1980.PubMedGoogle Scholar
  9. 9.
    Houghton JA and Houghton PJ: 5-Fluorouracil in combination with hypoxanthine and allopurinol: toxicity and metabolism in xenografts of human colonic carcinomas in mice. Biochem Pharmacol 29:2077–2080, 1980.PubMedCrossRefGoogle Scholar
  10. 10.
    Cadman E, Heimer R, and Davis L: Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism. Science 205:1135–1137, 1979.PubMedCrossRefGoogle Scholar
  11. 11.
    Lynch G, Kemeny N, Chun H, Martin DS, and Young C: Phase I evaluation and pharmacokinetic study of weekly i.v. thymidine and 5-FU in patients with advanced colorectal carcinoma. Cancer Treat Rep 69:179–184, 1985.PubMedGoogle Scholar
  12. 12.
    Fox RM, Woods RL, Tattersall MHN, and Brodie GM: Allopurinol modulation of high-dose Fluorouracil toxicity. Lancet 1:677, 1979.PubMedCrossRefGoogle Scholar
  13. 13.
    Howell SB, Wung W, and Tamerius R: Modulation of 5-fluorouracil (FU) toxicity by allopurinol (HPP) in man. Proc Am Assoc Cancer Res 21:336, 1980.Google Scholar
  14. 14.
    Canobbio L, Nobile MT, Ardizoni A, Tatarek R, and Rosso R: Phase II study of sequential methotrexate and 5-FU combination in the treatment of advanced colorectal cancer. Cancer Treat Rep 70:419–420, 1986.PubMedGoogle Scholar
  15. 15.
    Houghton JA and Taylor DM: Maintenance of biological and biochemical characteristics of human colorectal tumours during serial passage in immune-deprived mice. Br J Cancer 37:199–212, 1978.PubMedCrossRefGoogle Scholar
  16. 16.
    Houghton JA and 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Heidelberger C: Fluorinated pyrimidines and their nucleosides. In: Handbook of experimental pharmacology: antineoplastic and immunosuppressive agents, vol 38, AC Sartorelli and DG Johns (eds). Berlin: Springer, pp 193–231, 1974.Google Scholar
  18. 18.
    Danenberg PV: Thymidylate synthetase: a target enzyme in cancer chemotherapy. Biochim Biophys Acta 473:73–92, 1977.PubMedGoogle Scholar
  19. 19.
    Santi DV: Perspectives on the design and biochemical pharmacology of inhibitors of thymidylate synthetase. J Med Chem 23:103–111, 1980.PubMedCrossRefGoogle Scholar
  20. 20.
    Cohen SS: On the nature of thymineless death. Ann NY Acad Sci 186:292–301, 1971.CrossRefGoogle Scholar
  21. 21.
    Linder A: Cytochemical effects of 5-fluorouracil on sensitive and resistant Ehrlich ascites tumor cells. Cancer Res 19:189–195, 1959.Google Scholar
  22. 22.
    Ayusawa D, Shimizu K, Kayama H, Takeishi K, and Seno T: Accumulation of DNA strand breaks during thymineless death in thymidylate synthase-negative mutants of mouse FM3A cells. J Biol Chem 258:12,448–12,454, 1983.Google Scholar
  23. 23.
    Yoshioka A, Tanaka S, Hiraoka O, et al.: Deoxyribonucleoside triphosphate imbalance. J Biol Chem 262:8235–8241, 1987.PubMedGoogle Scholar
  24. 24.
    Cohen MB and Glazer RI: Cytotoxicity and inhibition of ribosomal RNA processing in human colon carcinoma cells. Mol Pharmacol 27:308–313, 1985.Google Scholar
  25. 25.
    Wilkinson DS and Pitot HC: Inhibition of ribosomal ribonucleic acid maturation in Novikoff hepatoma cells by 5-fluorouracil and 5-fluorouridine. J Biol Chem 248:63–68, 1973.PubMedGoogle Scholar
  26. 26.
    Will CL and Dolnick BJ: 5-Fluorouracil (FU) modifies mRNA processing in methotrexate-resistant KB cells. Proc Am Assoc Cancer Res 28:17, 1987.Google Scholar
  27. 27.
    Tseng WC, Medina D, and Randerath K: Specific inhibition of RNA methylation and modification in tissues of mice treated with 5-fluorouracil. Cancer Res 38:1250–1257, 1978.PubMedGoogle Scholar
  28. 28.
    Armstrong RD, Takimoto CH, and Cadman EC: Fluoropyrimidine-mediated changes in small nuclear RNA. J Biol Chem 261:21–24, 1986.PubMedGoogle Scholar
  29. 29.
    Dolnick BJ and Pink JJ: Effects of 5-fluorouracil on dihydrofolate reductase and dihydro-folate reductase mRNA from methotrexate-resistant KB cells. J Biol Chem 260:3006–3014, 1985.PubMedGoogle Scholar
  30. 30.
    Kufe DW, Major PP, Egan EM, and Loh E: 5-Fluoro-2′-deoxyuridine incorporation in L1210 DNA. J Biol Chem 256:8885–8888, 1981.PubMedGoogle Scholar
  31. 31.
    Schuetz JD, Wallace HJ, and Diasio RB: 5-Fluorouracil incorporation into DNA of CF-1 mouse bone marrow cells as a possible mechanism of toxicity. Cancer Res 44:1358–1363, 1984.PubMedGoogle Scholar
  32. 32.
    Ingraham HA, Tseng BY, and Goulian M: Mechanism for exclusion of 5-fluorouracil from DNA. Cancer Res 40:998–1001, 1980.PubMedGoogle Scholar
  33. 33.
    Goulian M, Bleille B, and Tseng BY: Methotrexate-induced misincorporation of uracil into DNA. Proc Natl Acad Sci USA 77:1956–1960, 1980.PubMedCrossRefGoogle Scholar
  34. 34.
    Evans RM, Laskin JD, and Hakala MT: Assessment of growth-limiting events caused by 5-fluorouracil in mouse cells and in human cells. Cancer Res 40:4113–4122, 1980.PubMedGoogle Scholar
  35. 35.
    Houghton PJ, Houghton JA, Germain G, and Torrance PM: Development and characterization of a human colon adenocarcinoma xenograft deficient in thymidine salvage. Cancer Res 47:2117–2122, 1987.PubMedGoogle Scholar
  36. 36.
    Houghton JA, Maroda SJ, Phillips JO, and Houghton PJ: Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in human colorectal adenocarcinoma xenografts. Cancer Res 41:144–149, 1981.PubMedGoogle Scholar
  37. 37.
    Houghton JA, Weiss KD, Williams LG, Torrance PM, and Houghton PJ: Relationship between 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate, and thymidylate synthase activity subsequent to 5-fluorouracil administration, in xenografts of human colon adenocarcinomas. Biochem Pharmacol 35:1351–1358, 1986.PubMedCrossRefGoogle Scholar
  38. 38.
    Houghton JA, Houghton PJ, and Wooten RS: Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine and 5-fluoro-2′-deoxyuridine. Cancer Res 39:2406–2413, 1979.PubMedGoogle Scholar
  39. 39.
    Hartman KU and Heidelberger C: Studies on fluorinated pyrimidines. XIII. Inhibition of thymidylate synthetase. J Biol Chem 236:3006–3013, 1961.Google Scholar
  40. 40.
    Reyes P and Heidelberger C: Fluorinated pyrimidines. XXVI. Mammalian thymidylate synthetase: its mechanism of action and inhibition by fluorinated nucleotides. Mol Pharmacol 1:14–30, 1965.PubMedGoogle Scholar
  41. 41.
    Santi DV, McHenry CS, and Sommer H: Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13:471-481, 1974.PubMedCrossRefGoogle Scholar
  42. 42.
    Lockshin A and Danenberg PV: Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol 30:247–257, 1981.PubMedCrossRefGoogle Scholar
  43. 43.
    Washtien WL and Santi DV: Assay of intracellular free and macromolecular-bound metabolites of 5-fluorodeoxyuridine and 5-fluorouracil. Cancer Res 39:3397–3404, 1979.PubMedGoogle Scholar
  44. 44.
    Spears CP, Shahinian AH, Moran RG, Heidelberger C, and Corbett TH: In vivo kinetics of thymidylate synthetase inhibition in 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas. Cancer Res 42:450–456, 1980.Google Scholar
  45. 45.
    Danenberg PV and 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.PubMedCrossRefGoogle Scholar
  46. 46.
    Houghton JA, Torrance PM, Radparvar S, Williams LG, and Houghton PJ: Binding of 5-fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts. Eur J Cancer Clin Oncol 22:505–510, 1986.PubMedCrossRefGoogle Scholar
  47. 47.
    Jackson RC and Harrap KR: Studies with a mathematical model of folate metabolism. Arch Biochem Biophys 158:827–841, 1973.PubMedCrossRefGoogle Scholar
  48. 48.
    Moran RG, Werkheiser WC, and Zakrzewski SF: Folate metabolism in mammalian cells in culture. I. Partial characterization of the folate derivatives present in L1210 mouse leukemia cells. J Biol Chem 254:3569–3575, 1976.Google Scholar
  49. 49.
    Brown JP, Davidson GE, and Scott JM: The identification of the forms of folate found in the liver, kidney and intestine of the monkey and their biosynthesis from pteroylglutamate (folic acid). Biochim Biophys Acta 343:78–88, 1974.PubMedGoogle Scholar
  50. 50.
    Eto I and Krumdieck CL: Determination of three different pools of reduced one-carbon-substituted folates. II. Quantitation and chain-length determination of the pteroylpolyglu-tamates of rat liver. Anal Biochem 115:138–146, 1981.PubMedCrossRefGoogle Scholar
  51. 51.
    Foo SK and Shane B: Regulation of folylpoly-gamma-glutamate synthesis in mammalian cells: in vitro and vivo synthesis of pteroylpoly-gamma-glutamates by Chinese hamster ovary cells. J Biol Chem 257:13,587–13,592, 1982.Google Scholar
  52. 52.
    Leslie GI and Baugh CM: The uptake of pteroyl (14-C)glutamic acid into rat liver and its incorporation into the natural pteroyl poly-gamma-glutamates of that organ. Biochemistry 13:4957–4961, 1974.PubMedCrossRefGoogle Scholar
  53. 53.
    McBurney MW and Whitmore GF: Characterization of a Chinese hamster cell with a temperature-sensitive mutation in folate metabolism. Cell 2:183–188, 1974.PubMedCrossRefGoogle Scholar
  54. 54.
    Taylor RT and Hanna ML: Folate-dependent enzymes in cultured Chinese hamster cells: folylpolyglutamate synthetase and its absence in mutants auxotrophic for glycine + adenosine + thymidine. Arch Biochem Biophys 181:331–334Google Scholar
  55. 55.
    Baggott JE and Krumdieck CL: Folylpoly-y-glutamates as cosubstrates for 10-formyltetra-hydrofolate: 5’-phosphoribosyl-5-amino-4-imidazole-carboxamide formyl transferase. Biochemistry 18:1036–1041, 1979.PubMedCrossRefGoogle Scholar
  56. 56.
    Cheng FW, Shane B, and Stokstad ELR: Pentaglutamate derivatives of folate as substrates for rat liver tetrahydropteroyl glutamate methyltransferase and 5, 10-methylenetetrahydrofolate reductase. Can J Biochem 53:1020–1027, 1975.CrossRefGoogle Scholar
  57. 57.
    Coward JK, Parameswaran KN, Cashmore AR, and Bertino JR: 7,8-Dihydropteroyl oligo-gamma-L-glutamates: synthesis and kinetic studies with purified dihydrofolate reductase from mammalian sources. Biochemistry 13:3899–3903, 1974.PubMedCrossRefGoogle Scholar
  58. 58.
    Curthoys NP and Rabinowitz JC: Formyltetrahydrofolate synthetase: binding of folate substrates and kinetics of the reverse reaction. J Biol Chem 247:1965–1971, 1972.PubMedGoogle Scholar
  59. 59.
    Kisliuk RL, Gaumont Y, Lafer E, Baugh CM, and Montgomery JA: Polyglutamyl derivatives of tetrahydrofolate as substrates for Lactobacillus casei thymidylate synthase. Biochemistry 20:929–934, 1981.PubMedCrossRefGoogle Scholar
  60. 60.
    Mackenzie RE and Baugh CM: Tetrahydropteroylpolyglutamate derivatives as substrates of two multifunctional proteins with folate-dependent enzyme activities. Biochim Biophys Acta 611:187–195, 1980.PubMedGoogle Scholar
  61. 61.
    Matthews RG and Baugh CM: Interactions of pig liver methylenetetrahydrofolate reductase with methylenetetrahydropteroyl polyglutamate substrates and with dihydropteroyl poly-glutamate inhibitors. Biochemistry 19:2040–2045, 1980.PubMedCrossRefGoogle Scholar
  62. 62.
    Lu Y-Z, Aiello PD, and Matthews RG: Studies on the polyglutamate specificity of thymidylate synthase from fetal pig liver. Biochemistry 23:6870–6876, 1984.PubMedCrossRefGoogle Scholar
  63. 63.
    Dwivedi CM, Kisliuk RL, and Baugh CM: The interaction of pteroylpolyglutamates with calf thymus thymidylate synthase. In: Folyl and antifolyl polyglutamates, ID Goldman, BA Chabner, and JR Bertino (eds). New York: Plenum, pp 65–70, 1983.Google Scholar
  64. 64.
    McGuire JJ and Bertino JR: Enzymatic synthesis and function of folylpolyglutamates. Mol Cell Biochem 38:19–48, 1981.PubMedCrossRefGoogle Scholar
  65. 65.
    Kisliuk RL, Gaumont Y, and Baugh CM: Polyglutamyl derivatives of folate as substrates and inhibitors of thymidylate synthetase. J Biol Chem 249:4100–4103, 1974.PubMedGoogle Scholar
  66. 66.
    Dolnick BJ and Cheng Y: Human thymidylate synthetase. II. Derivatives of pteroyl mono-and -polyglutamates as substrates and inhibitors. J Biol Chem 253:3563–3567, 1978.PubMedGoogle Scholar
  67. 67.
    Coward JK, Chello PC, Cashmore AR, Parameswaran KN, De Angelis LM, and Bertino JR: 5-Methyl-5,6,7,8-tetrahydropteroyl oligo-gamma-L-glutamates: synthesis and kinetic studies with methionine synthetase from bovine brain. Biochemistry 14:1548–1552, 1975.PubMedCrossRefGoogle Scholar
  68. 68.
    Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, and Jolivet J: Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem 260:9720–9726, 1985.PubMedGoogle Scholar
  69. 69.
    Cheng Y-C, Dutschman GE, Starnes MC, Fisher MH, Nanavathi T, and Nair MG: Activity of the new antifolate N10-propargyl-5,8-dideazafolate and its polyglutamates against human dihydrofolate reductase, human thymidylate synthetase, and KB cells containing different levels of dihydrofolate reductase. Cancer Res 45:598–600, 1985.PubMedGoogle Scholar
  70. 70.
    Radparvar S, Houghton PJ, and Houghton JA: Characteristics of thymidylate synthase purified from a human colon adenocarcinoma. Arch Biochem Biophys 260:342–350, 1988.PubMedCrossRefGoogle Scholar
  71. 71.
    Yin M-B, Zakrzewski SF, and Hakala MT: Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil. Mol Pharmacol 32:190–197, 1983.Google Scholar
  72. 72.
    Priest DG and Mangum M: Relative affinity of 5, 10-methylenetetrahydrofolylpolyglu-tamates for the Lactobacillus casei thymidylate synthetase-5-fluorodeoxyuridylate binary complex. Arch Biochem Biophys 210:118–123, 1981.PubMedCrossRefGoogle Scholar
  73. 73.
    Danenberg PV and Lockshin A: Tight-binding complexes of thymidylate synthetase, folate analogs, and deoxyribonucleotides. Adv Enzyme Regul 20:99–110, 1982.PubMedCrossRefGoogle Scholar
  74. 74.
    Priest DG, Happel KK, Mangum M, Bednarek JM, Doig MT, and Baugh CM: Tissue folyl-polyglutamate chain-length characterization by electrophoresis as thymidylate synthetase-fluorodeoxyuridylate ternary complexes. Anal Biochem 115:163–169, 1981.PubMedCrossRefGoogle Scholar
  75. 75.
    Ullman B, Lee M, Martin DW, and Santi DV: Cytotoxicity of 5-fluoro-2′-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 75:980–983, 1978.PubMedCrossRefGoogle Scholar
  76. 76.
    Kayomarsi K and Moran RG: Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res 46:5229–5235, 1986.Google Scholar
  77. 77.
    Waxman S and Bruckner H: The enhancement of 5-fluorouracil antimetabolic activity by leucovorin, menadione and α-tocopherol. Eur J Cancer Clin Oncol 18:685–692, 1982.PubMedCrossRefGoogle Scholar
  78. 78.
    Evans RM, Laskin JD, and Hakala MT: Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 41:3288–3295, 1981.PubMedGoogle Scholar
  79. 79.
    Berger SH and Hakala MT: Relationship of dUMP and free FdUMP pools to inhibition of thymidylate synthase by 5-fluorouracil. Mol Pharmacol 25:303–309, 1984.PubMedGoogle Scholar
  80. 80.
    Mini E, Moroson BA, and Bertino JR: Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells: enhancement by leucovorin. Cancer Treat Rep 71: 381–389, 1987.PubMedGoogle Scholar
  81. 81.
    Nahas A, Nixon PF, and Bertino JR: Uptake and metabolism of N5-formyltetrahydrofolate by L1210 leukemia cells. Cancer Res 32:1416–1421, 1972.PubMedGoogle Scholar
  82. 82.
    Matherly LH, Barlowe CK, and Goldman ID: Antifolate polyglutamylation and competitive drug displacement at dihydrofolate reductase as important elements in leucovorin rescue in L1210 cells. Cancer Res 46:588–593, 1986.PubMedGoogle Scholar
  83. 83.
    Spears CP, Gustavsson BG, Mitchell MS, et al.: Thymidylate synthetase inhibition in malignant tumors and normal liver of patients given intravenous 5-fluorouracil. Cancer Res 44:4144–4150, 1984.PubMedGoogle Scholar
  84. 84.
    Klubes P, Cerna I, and Meldon MA: Effect of concurrent calcium leucovorin infusion on 5-fluorouracil cytotoxicity against murine L1210 leukemia. Cancer Chemother Pharmacol 6:121–125, 1981.PubMedCrossRefGoogle Scholar
  85. 85.
    Ardalan B, Buscaglia MD, and Schein PS: Tumor 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response. Biochem Pharmacol 27:2009–2013, 1978.PubMedCrossRefGoogle Scholar
  86. 86.
    Jackson RC: The regulation of thymidylate biosynthesis in Novikoff hepatoma cells and the effects of amethopterin, 5-fluorodeoxyuridine and 3-deazauridine. J Biol Chem 253:7440–7446, 1978.PubMedGoogle Scholar
  87. 87.
    Moran RG, Spears CP, and Heidelberger C: Biochemical determinants of tumor sensitivity to 5-fluorouracil: ultrasensitive methods for the determination of 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate and thymidylate synthetase. Proc Natl Acad Sci USA 16:1456–1460, 1979.CrossRefGoogle Scholar
  88. 88.
    Myers CE, Young RC, and Chabner BA: Biochemical determinants of 5-fluorouracil response in vivo: the role of deoxyuridylate pool expansion. J Clin Invest 56:1231–1238, 1975.PubMedCrossRefGoogle Scholar
  89. 89.
    Washtien WL: Thymidylate synthetase levels as a factor in 5-fluorodeoxyuridine and methotrexate cytotoxicity in gastrointestinal tumor cells. Mol Pharmacol 21:723–728, 1982.PubMedGoogle Scholar
  90. 90.
    Machover D, Schwarzenberg L, Goldschmidt E, et al.: Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high dose folinic acid. Cancer Treat Rep 66:1803–1807, 1982.PubMedGoogle Scholar
  91. 91.
    Cunningham J, Bukowski RM, Budd GT, Weick JK, and Purvis J: 5-Fluorouracil and folinic acid: a phase I-II trial in gastrointestinal malignancy. Invest New Drugs 2:391–395, 1984.PubMedCrossRefGoogle Scholar
  92. 92.
    Madajewicz S, Petrelli N, Rustum YM, et al.: Phase I-II trial of high-dose calcium leu-covorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res 44:4667–4669, 1984.PubMedGoogle Scholar
  93. 93.
    Machover D, Goldschmidt E, Chollet P, et al.: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4:685–696, 1986.PubMedGoogle Scholar
  94. 94.
    Doroshow JH, Bertrand M, Multhauf P, et al.: Prospective randomized trial comparing 5-FU versus (vs) 5-FU and high dose folinic acid (HDFA) for treatment of advanced colorectal cancer. Proc Am Soc Clin Oncol 6:96, 1987.Google Scholar
  95. 95.
    Petrelli N, Madajewicz S, Herrera L, et al.: A survival study of 5-fluorouracil (5-FU) and high dose leucovorin (CF) in metastatic colorectal carcinoma. Proc Am Soc Clin Oncol 4: 76, 1985.Google Scholar
  96. 96.
    Petrelli N, Herrera L, Stulc J, Rustum Y, and Mittelman A: A phase III study of 5-fluorouracil (5-FU) versus 5-FU + methotrexate (MTX) versus 5-FU + high dose leucovorin (CF) in metastatic colorectal adenocarcinoma. Proc Am Soc Clin Oncol 6:74, 1987.Google Scholar
  97. 97.
    Allegra C, Sholar PW, Drake JC, Bagley C, Lippman ME, and Chabner BA: A phase II trial for the treatment of metastatic breast cancer with 5-fluorouracil (5-FU) and leucovorin. In: Proceedings: development of folates and folic acid antagonists in cancer chemotherapy. Tarpon Springs FL, p 23, 1986.Google Scholar
  98. 98.
    Erlichman C, Fine S, Wong A, and Elkhaim T: A comparison of 5-fluorouracil (5FU) and folinic acid (FA) versus 5FU in metastatic colorectal carcinoma (MCC). Proc Am Soc Clin Oncol 5:82, 1986.Google Scholar
  99. 99.
    Valone F, Kohler M, Fisher K, and Hannigan J: A NCOG randomized trial of 5-FU vs leucovorin (LV) + 5-FU vs methotrexate (MTX), 5-Fu, LV for advanced colon cancer. In: Proceedings: development of folates and folic acid antagonists in cancer chemotherapy. Tarpon Springs FL, p 20, 1986.Google Scholar
  100. 100.
    O’Connell MJ: Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (FA): clinical studies in colon cancer. In: Proceedings: development of folates and folic acid antagonists in cancer chemotherapy. Tarpon Springs FL, p 21, 1986.Google Scholar
  101. 101.
    Herrera-Ornelas L, Petrelli N, Trave F, et al.: Toxicity and pharmacokinetics of 5-fluorouracil (FU) and high dose citrovorum factor (HDCF) administered by continuous intravenous infusion for 5 days to patients (pts) with advanced colorectal cancer. Proc Am Soc Clin Oncol 5:39, 1986.Google Scholar
  102. 102.
    Trave F, Frank C, Petrelli N, Herrera L, Mittelman A, and Rustum Y: Pharmacokinetics of folates in patients with colorectal carcinoma. Proc Am Assoc Cancer Res 27:171, 1986.Google Scholar
  103. 103.
    Newman E, Doroshow J, Bertrand M, et al.: Pharmacokinetics of high-dose folinic acid (d1-CF) administered by continuous intravenous (iv) infusion. Proc Am Assoc Cancer Res 26:158, 1985.Google Scholar
  104. 104.
    Rustum Y, Trave F, Petrelli N, Herrera L, and Mittelman A: Modulation of reduced folates in tumor tissue of colon cancer patients (pts). Proc Am Assoc Cancer Res 28:229, 1987.Google Scholar
  105. 105.
    Straw JA, Szapary D, and Wynn WT: Pharmacokinetics of the diastereoisomers of leu-covorin alter intravenous and oral administration to normal subjects. Cancer Res 44:3114–3119, 1984.PubMedGoogle Scholar
  106. 106.
    Blakley RL: The biochemistry of folic acid and related pteridines. New York: American Elsevier, p 82, 1969.Google Scholar
  107. 107.
    White JC, Bailey BD, and Goldman ID: Lack of stereospecificity at carbon 6 of methyltet-rahydrofolate transport in Ehrlich ascites tumor cells. J Biol Chem 253:242–245, 1978.PubMedGoogle Scholar
  108. 108.
    Sirotnak FM, Chello PL, Moccio DM, Kisliuk RL, Combepine G, Gaumont Y, and Montgomery JA: Stereospecificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexate in vitro. Biochem Pharmacol 28: 2993–2997, 1979.PubMedCrossRefGoogle Scholar
  109. 109.
    McGuire JJ, Hsieh P, Coward JK, and Bertino JR: Enzymatic synthesis of folylpolyglu-tamates. J Biol Chem 255:5776–5788, 1980.PubMedGoogle Scholar
  110. 110.
    Sato JK, Newman EM, and Moran RG: Preparation of [6R]-tetrahydrofolic acid and [6R]-5-formyltetrahydrofolic acid of high stereochemical purity. Anal Biochem 154:516–524, 1986.PubMedCrossRefGoogle Scholar
  111. 111.
    Allen S, Fine S, and Erlichman C: A phase II trial of 5-fluorouracil (5FU) and folinic acid (FA) plus dipyridamole. Proc Am Soc Clin Oncol 6:95, 1987.Google Scholar
  112. 112.
    Scanlon KJ, Newman EM, Lu Y, and Priest DG: Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923–8925, 1986.PubMedCrossRefGoogle Scholar
  113. 113.
    Galligioni E, Canobbio L, Figoli F, Fassio T, Frustaci S, Givellari D, Vaccher E, Lo Re G, Gasparini G, Veronesi A, and Monfardini S: Cisplatin and 5-fluorouracil combination chemotherapy in advanced and/or metastatic colorectal carcinoma: a phase II study. Eur J Cancer Clin Oncol 23:657–661, 1987.PubMedCrossRefGoogle Scholar
  114. 114.
    Cantrell JE, Hart RD, Taylor RF, and Harvey JH: Pilot trial of prolonged continuous infusion 5-fluorouracil and weekly cisplatin in advanced colorectal cancer. Cancer Treat Rep 71:615–618, 1987.PubMedGoogle Scholar
  115. 115.
    Rooney M, Kish J, Jacobs J, Kinzie J, Weaver A, Crissman J, and Al-Sarraf M: Improved complete response rate and survival in advanced head and neck cancer after three course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 55:1123–1128, 1985.PubMedCrossRefGoogle Scholar
  116. 116.
    Houghton JA, Schmidt C, and Houghton PJ: The effect of derivatives of folic acid on the fluorodeoxyuridylate-thymidylate synthetase covalent complex in human colon xenografts. Eur J Cancer Clin Oncol 18:347–354, 1982.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1989

Authors and Affiliations

  • Janet A. Houghton
  • Peter J. Houghton

There are no affiliations available

Personalised recommendations