Thymidylate Synthetase Inhibitors: Experimental and Clinical Aspects

  • Ann L. Jackman
  • Terence R. Jones
  • A. Hilary Calvert
Part of the Cancer Treatment and Research book series (CTAR, volume 24)


The enzyme thymidylate synthetase (TS) which accomplishes the methylation of deoxyuridine monophosphate to thymidine monophosphate has been of interest ever since its discovery in 1957 [1]. Its crucial role in the synthesis of the only nucleotide required exclusively for DNA synthesis makes it an obvious target for antimetabolite attack. The discovery by Cohen [2] that 5-fluorodeoxyuridine monophosphate (FdUMP), a metabolite of the antipyrimidines 5-fluorouracil and 5-fluorodeoxyuridine, was a potent inhibitor of TS, coupled with the documentation of clinical antitumour activity for this drug ensured the continuing studies both of TS and antipyrimidines. The detailed and painstaking studies of the nature of the tight binding of FdUMP to TS in the presence of the cofactor 5,10-CH2FH4, to produce a stable ternary complex have given us enormous insights into the mechanism of TS catalysis and have allowed the rational design of further TS-inhibitory uracil derivatives. The inhibition of TS by FdUMP was accepted for many years as the main basis for the cytotoxicity of the fluorinated pyrimidines, and only recently have the incorporations of these molecules into nucleic acids been fully considered as alternative or contributory cytotoxic events. The knowledge that FU has cytotoxic actions unrelated to TS inhibition implies that an inhibition of TS uncomplicated by other actions has not been evaluated as an antitumour event.


Ehrlich Ascites Carcinoma Cell Thymidylate Synthetase Tetrahydrofolic Acid Folate Analogue Bridge Region 
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  1. 1.
    Friedkin M, Kornberg A: The enzymatic conversion of deoxyuridylic acid to thymidylic acid and the participation of tetrahydrofolic acid. In: The chemical basis of heredity, McElroy WD, Glass B (eds). Baltimore: The John Hopkins Press, pp 609–614, 1957.Google Scholar
  2. 2.
    Cohen SS, Flaks JG, Barner HD, Loeb MR, Lichtenstein J: The mode of action of 5-fluorouracil and its derivatives. Proc Natl Acad Sci USA 44:1004–1012, 1958.PubMedGoogle Scholar
  3. 3.
    Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA: Temporary remissions in acute leukaemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). New Eng J Med 238:787–793, 1948.PubMedGoogle Scholar
  4. 4.
    Futterman S: Enzymatic reduction of folic acid and dihydrofolic acid to tetrahydrofolic acid: J Biol Chem 288:1031–1038, 1957.Google Scholar
  5. 5.
    Woods DD: The relation of p-aminobenzoic acid to the mechanism of the action of sulphanilamide. Brit J Exptl Pathol 21:74–90, 1940.Google Scholar
  6. 6.
    Blakley RL: The biochemistry of folic acid and related pteridines. Amsterdam: North Holland publishing Company, 1969.Google Scholar
  7. 7.
    Friedkin M: Thymidylate synthetase, Adv Enzymol 38:235–292, 1973.PubMedGoogle Scholar
  8. 8.
    Danenberg PV: Thymidylate synthetase — a target enzyme in cancer chemotherapy. Bio-chim Biophys Acta 473:73–92, 1977.Google Scholar
  9. 9.
    Danenberg PV, Lockshin A: Fluorinated pyrimidines as tight-binding inhibitors of thymidylate synthetase. Pharmac Ther 13:69–90, 1981.Google Scholar
  10. 10.
    Lewis JR CA, Dunlap RB: Thymidylate synthetase and its interaction with 5-fluoro-2′-deoxyuridylate. In: Topics in molecular pharmacology, Burgen ASV, Roberts GCK (eds). Amsterdam: Elsevier/North Holland Biomedical Press, 1981, pp 169–219.Google Scholar
  11. 11.
    Maley F, Maley GF: Studies on identifying the locus of action of fluorouracil. In: Molecular actions and targets for cancer chemotherapeutic agents, Sartorelli AC, Lazo JS, Bertino JR (eds). New York: Academic Press, pp 265–283, 1981.Google Scholar
  12. 12.
    Santi DV: Inhibition of thymidylate synthetase: Mechanism, methods and metabolic consequences. In: Molecular actions and targets for cancer chemotherapeutic agents, Sartorelli AC, Lazo JS, Bertino JR (eds). New York: Academic Press, pp 285–300, 1981.Google Scholar
  13. 13.
    Danenberg PV, Lockshin A: Thymidylate synthetase — substrate complex formation. Mol Cellul Biochem 43:49–57, 1982.Google Scholar
  14. 14.
    Jencks WP: Mechanism and catalysis of simple carbonyl group reactions. Prog Phys Org Chem 2:63–128, 1964.Google Scholar
  15. 15.
    Pogolotti Jr AL, Ivanetich KM, Sommer H, Santi DV: Thymidylate synthetase: Studies on the peptide containing covalently bound 5-fluoro-2′-deoxyuridylate and 5,10-methylenete-trahydrofolate. Biochem Biophys Res Comm 70:972–978, 1976.PubMedGoogle Scholar
  16. 16.
    Pastore EJ, Friedkin M: The enzymatic synthesis of thymidylate. J Biol Chem 237:3802–3810, 1962.PubMedGoogle Scholar
  17. 17.
    Blakley RL, Ramasastri BV, McDougall BM: The biosynthesis of thymidylic acid. J Biol Chem 238:3075–3097, 1963.PubMedGoogle Scholar
  18. 18.
    Tatum C, Vederas J, Schleicher E, Benkovic SJ, Floss H: Stereospecifity of thymidylate synthetase. J Chem Soc Chem Comm:218–220, 1977.Google Scholar
  19. 19.
    Slieker LJ, Benkovic SJ: Synthesis of (6R, 11S)- and (6R, 11R)-5,10-methylene[11-1H,2H]tetrahydrofolate. Stereochemical paths of serine hydroxymethyltransferase, 5,10-methylenetetrahydrofolate dehydrogenase, and thymidylate synthetase catalysis. J Am Chem Soc 106:1833–1838, 1984.Google Scholar
  20. 20.
    Leary RP, Gaumont Y, Kisliuk RL: Effects of the diastereoisomers of methylenetrahydro-folate on the reaction catalysed by thymidylate synthetase. Biochem Biophys Res Comm 56:484–488, 1974.PubMedGoogle Scholar
  21. 21.
    Crusberg TC, Leary R, Kisliuk RL: Properties of thymidylate synthetase from dichlorom-ethotrexate-resistant Lactobacillus casei. J Biol Chem 245:5292–5296, 1970.PubMedGoogle Scholar
  22. 22.
    Reid VE, Friedkin M: Thymidylate synthetase in mouse erythrocytes infected with Plasmodium berghei. Mol Pharmacol 9:74–80, 1973.PubMedGoogle Scholar
  23. 23.
    Scanlon KJ, Cashmore AR, Moroson BA, Dreyer RN, Bertino JR: Inhibition of serine metabolism by tetrahydrohomofolate in L1210 mouse leukemia cells. Mol Pharmacol 19:481–490, 1981.PubMedGoogle Scholar
  24. 24.
    Taylor RT, Hanna ML: 5-Methyltetrahydrohomofolate: A substrate for cobalamin methyltransferases and an inhibitor of cell growth. Arch Biochem Biophys 163:122–132, 1974.PubMedGoogle Scholar
  25. 25.
    Plante LT, Crawford EJ, Friedkin M: Enzyme studies with new analogues of folic acid and homofolic acid. J Biol Chem 242:1466–1475, 1967.PubMedGoogle Scholar
  26. 26.
    Plante LT, Crawford EJ, Friedkin M: Polyglutamyl and polylysyl derivatives of the lysine analogues of folic acid and homofolic acid. J Med Chem 19:1295–1299, 1976.PubMedGoogle Scholar
  27. 27.
    Kisliuk RL, Strumpf D, Gaumont Y, Leary RP, Plante L: Diastereoisomers of 5,10-methylene-5,6,7,8-tetrahydropteroyl-D-glutamic acid. J Med Chem 20:1531–1533, 1977.PubMedGoogle Scholar
  28. 28.
    Lorenson MY, Maley GF, Maley F: The purification and properties of thymidylate synthetase from chick embryo extracts. J Biol Chem 242:3332–3344, 1967.PubMedGoogle Scholar
  29. 29.
    Dunlap RB, Harding NGL, Huennekens FM: Thymidylate synthetase from amethopterin-resistant Lactobacillus casei. Biochemistry 10:88–97, 1971.PubMedGoogle Scholar
  30. 30.
    Gupta VS, Meldrum JB: Purification and properties of thymidylate synthetase from pig thymus. Can J Biochem 50:352–362, 1972.PubMedGoogle Scholar
  31. 31.
    Kalman TI, Bloch A, Szekeres GL, Bardos TJ: Methylation of 4-thio-2′-deoxyuridylate by thymidylate synthetase. Biochem Biophys Res Comm 55:210–217, 1973.PubMedGoogle Scholar
  32. 32.
    Haertlé T, Wohlrab F, Guschlbauer W: Thymidylate synthetase from Escherichia coli Kl2. Eur J Biochem 102:223–230, 1979.PubMedGoogle Scholar
  33. 33.
    Galivan JH, Maley GF, Maley F: Factors affecting substrate binding in Lactobacillus casei thymidylate synthetase as studied by equilibrium dialysis. Biochemistry 15:356–362, 1976.PubMedGoogle Scholar
  34. 34.
    Daron HH, Aull JL: A kinetic study of thymidylate synthetase from Lactobacillus casei. J Biol Chem 253:940–945, 1978.PubMedGoogle Scholar
  35. 35.
    Dolnick BJ, Cheng YC: Human thymidylate synthetase derived from blast cells of patients with acute myelocytic leukemia. J Biol Chem 252:7697–7703, 1977.PubMedGoogle Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    Langenbach RJ, Danenberg PV, Heidelberger C: Thymidylate synthetase: mechanism of inhibition by 5-fluoro-2′-deoxyuridylate. Biochem Biophys Res Comm 48:1565–1571, 1972.PubMedGoogle Scholar
  38. 38.
    Lockshin A, Danenberg PV: Biochemical factors affecting the tightness of 5-fluorodeoxyu-ridylate binding to human thymidylate synthetase. Biochem Pharmacol 30:247–257, 1981.PubMedGoogle Scholar
  39. 39.
    Santi DV: Perspectives on the design and biochemical pharmacology of inhibitors of thymidylate synthetase. J Med Chem 23:103–111, 1980.PubMedGoogle Scholar
  40. 40.
    De Clercq E, Balzarini J, Torrence PF, Mertes MP, Schmidt CL, Shugar D, Barr PJ, Jones AS, Verhelst G, Walker RT: Thymidylate synthetase as target enzyme for the inhibitory activity of 5-substituted 2′-deoxyuridines on mouse leukaemia L1210 cell growth. Mol Pharmacol 19:321–330, 1981.PubMedGoogle Scholar
  41. 41.
    Wataya Y, Santi DV, Hansch C: Inhibition of Lactobacillus casei thymidylate synthetase by 5-substituted 2′,-deoxyuridylates. Preliminary structure-activity relationship. J Med Chem 20:1469–1473, 1977.PubMedGoogle Scholar
  42. 42.
    De Clercq E, Balzarini J, Chang CT-C, Bigge CF, Kalaritis P, Mertes MP: 5(e)-(3-Azidos-tyryl)-2′,-deoxyuridine 5′-phosphate is a photo-activated inhibitor of thymidylate synthetase. Biochem Biophys Res Comm 97:1068–1075, 1980.PubMedGoogle Scholar
  43. 43.
    De Clercq E, Balzarini J, Descamps J, Bigge CF, Chang CT-C, Kalaritis P, Mertes MP: Antiviral, antitumour and thymidylate synthetase inhibition studies of 5-substituted styryl derivatives of 2′,-deoxyuridine and their 5′-phosphates. Biochem Pharmacol 30:495–502, 1981.PubMedGoogle Scholar
  44. 44.
    Maggiora L, Chan CT-C, Hasson ME, Bigge CF, Mertes MP: 5-p-Benzoquinonyl-2′-deox-yuridine 5′-phosphate: A possible mechanism-based inhibitor of thymidylate synthetase. J Med Chem 26:1028–1036, 1983.PubMedGoogle Scholar
  45. 45.
    Barr PJ, Nolan PA, Santi DV, Robins MJ: Inhibition of thymidylate synthetase by 5-alkynyl-2′-deoxyuridylates. J Med Chem 24:1385–1388, 1981.PubMedGoogle Scholar
  46. 46.
    Danenberg PV, Bhatt RS, Kundu NG, Danenberg KD, Heidelberger C: Interaction of 5-ethynyl-2′-deoxyuridylate with thymidylate synthetase. J Med Chem 24:1537–1540, 1981.PubMedGoogle Scholar
  47. 47.
    Barr PJ, Robins MJ, Santi DV: Reaction of 5-ethynyl-2′-deoxyuridylate with thiols and thymidylate synthetase. Biochemistry 22:1696–1703, 1983.PubMedGoogle Scholar
  48. 48.
    Maggiora L, Chang CT-C, Torrence PF, Mertes MP: 5-Nitro-2′,-deoxyuridine 5′-phos-phate: A mechanism-based inhibitor of thymidylate synthetase. J Am Chem Soc 103:3192–3198, 1981.Google Scholar
  49. 49.
    Washtien WL, Santi DV: Mechanism of action of 5-Nitro-2′-deoxyuridine. J Med Chem 25:1252–1255, 1982.PubMedGoogle Scholar
  50. 50.
    Kalman TI, Goldman D: Inactivation of thymidylate synthetase by a novel mechanism-based enzyme inhibitor: l-(beta-D-2′,-Deoxyribofuranosyl)8-azapurin-2-one 5′-monophos-phate. Biochem Biophys Res Comm 102:682–689, 1981.PubMedGoogle Scholar
  51. 51.
    Kisliuk RL, Levine MD: Properties of reduced derivatives of aminopterin. J biol Chem 239:1900–1904, 1964.PubMedGoogle Scholar
  52. 52.
    Horwitz SB, Kisliuk RL: Reduced derivatives of methotrexate. J Med Chem 11:907–908, 1968.PubMedGoogle Scholar
  53. 53.
    Horwitz SB, Kwok G, Wilson L, Kisliuk RL: Diastereoisomers of formaldehyde derivatives of tetrahydrofolic acid and tetrahydroaminpterin. J Med Chem 12:49–51, 1969.PubMedGoogle Scholar
  54. 54.
    Goodman L, DeGraw J, Kisliuk RL, Friedkin M, Pastore EJ, Crawford EJ, Plante LT, Al-Hahas A, Morningstar Jr JF, Kwok G, Wilson L, Donovan EF, Ratzan J: Tetrahydro-homofolate, a specific inhibitor of thymidylate synthetase. J Am Chem Soc 86:308–309, 1964.Google Scholar
  55. 55.
    Livingston D, Crawford EJ, Friedkin M: Studies with tetrahydrohomofolate and thymidylate synthetase from amethopterin-resistant mouse leukemia cells. Biochemistry 7:2814–2818, 1968.PubMedGoogle Scholar
  56. 56.
    Slavik K, Zakrzewski SF: Inhibition of thymidylate synthetase by some analogs of tetrahydrofolic acid. Mol Pharmacol 3:370–377, 1967.PubMedGoogle Scholar
  57. 57.
    Temple JrC, Bennett Jr LL, Rose JD, Elliott RD, Montgomery JA, Mangum JH: Synthesis of pseudo cofactor analogues as potential inhibitors of the folate enzymes. J Med Chem 25:161–166, 1982.PubMedGoogle Scholar
  58. 58.
    DeGraw JI, Kisliuk RL, Gaumont Y, Baugh CM, Nair MG: Synthesis and antifolate activity of 10-deazaminopterin. J Med Chem 17:552–553, 1974.PubMedGoogle Scholar
  59. 59.
    DeGraw JI, Brown VH, Tagawa H, Kisliuk RL, Gaumont Y, Sirotnak FM: Synthesis and antitumour activity of 10-alkyl-l0-deazaminopterins. A convenient synthesis of 10-deazaminopterin. J Med Chem 25:1227–1230, 1982.PubMedGoogle Scholar
  60. 60.
    Kim YH, Gaumont Y, Kisliuk RL, Mautner HG: Synthesis and biological activity of 10-thia-l0-deaza analogs of folic acid, pteroic acid and related compounds. J Med Chem 18:776–780, 1975.PubMedGoogle Scholar
  61. 61.
    Nair MG, Chen SY, Kisliuk RL, Gaumont Y, Strumpf D: Folate analogues altered in the C9-N10 bridge region: 11-thiohomofolic acid. J Med Chem 22:850–855, 1979.PubMedGoogle Scholar
  62. 62.
    Nair MG, Chen SY, Kisliuk RL, Gaumont Y, Strumpf D: Folate analogues altered in the C9-N10 bridge region, synthesis and antifolate activity of 11-thiohomoaminopterin. J Med Chem 23:899–903, 1980.PubMedGoogle Scholar
  63. 63.
    Nair MG, Saunders C, Chen SY, Kisliuk RL, Gaumont Y: Folate analogues altered in the C9-N10 bridge region. 11-Oxahomofolic acid, a potential antitumour agent. J Med Chem 23:59–65, 1980.PubMedGoogle Scholar
  64. 64.
    Nair MG, Bridges TW, Henkel TJ, Kisliuk RL, Gaumont Y, Sirotnak FM: Folate analogues altered in the C9-N10 bridge region. Synthesis and antitumour evaluation of 11-oxa-homoaminopterin and related compounds. J Med Chem 24:1068–1073, 1981.PubMedGoogle Scholar
  65. 65.
    Nair MG, O’Neal PC, Baugh CM, Kisliuk RL, Gaumont Y, Rodman M: Folate analogues altered in the C9-N10 bridge region: N10-tosylisohomofolic acid and N10-tosylisohomoam-inopterin. J Med Chem 21:673–677, 1978.PubMedGoogle Scholar
  66. 66.
    Nair MG, Rozmyslovicz MK, Kisliuk RL, Gaumont Y, Sirotnak FM: The nor-analogues of folic acid. In: Chemistry and Biology of Pteridines, Blair JA (ed). Berlin: de Gruyter 1983, pp 121–126.Google Scholar
  67. 67.
    DeGraw JI, Kisliuk RL, Gaumont Y, Baugh CM: Antimicrobial activity of 8-deazafolic acid. J Med Chem 17:470–471, 1974.PubMedGoogle Scholar
  68. 68.
    Broom AD, Srinivasan A: Synthesis of an 8-deaza analog of the intermediate in the thymidylate synthetase reaction. In: Chemistry and Biology of Pteridines, Blair JA (ed). Berlin: de Gruyter, 1983, pp 445–449.Google Scholar
  69. 69.
    Nair MG, Salter OC, Kisliuk RL, Gaumont Y, North G: Folate analogues. Synthesis and biological evaluation of two analogues of dihydrofolic acid possessing a 7,8-dihydro-8-oxapterin ring system. J Med Chem 26:1164–1168, 1983.PubMedGoogle Scholar
  70. 70.
    Johne S: Search for pharmaceutically interesting quinazoline derivatives: Efforts and results (1969–1980). Prog Drug Res 26:259–341, 1982.PubMedGoogle Scholar
  71. 71.
    Bird OD, Vaitkus JW, Clarke J: 2-Amino-4-hydroxyquinazolines as inhibitors of thymidylate synthetase. Mol Pharmacol 6:573–575, 1970.PubMedGoogle Scholar
  72. 72.
    Carlin SC, Rosenberg RN, VandeVenter L, Friedkin M: Quinazoline antifolates as inhibitors of growth, dihydrofolate reductase and thymidylate synthetase of mouse neuroblastoma cells in culture. Mol Pharmacol 10:194–203, 1974.PubMedGoogle Scholar
  73. 73.
    McCuen RW, Sirotnak FM: Thymidylate synthetase from Diplococcus pneumoniae. Properties and inhibition by folate analogues. Biochim Biophys Acta 384:369–380, 1975.PubMedGoogle Scholar
  74. 74.
    Scanlon KJ, Rode W, Hynes JB: Use of a new biospecific absorbent for affinity chromatography to purify thymidylate synthetase from mouse leukemia cells, L1210. Proc Am Assoc Cancer Res 19:136, 1978.Google Scholar
  75. 75.
    Scanlon KJ, Moroson BA, Bertino JR, Hynes JB: Quinazoline analogues of folic acid as inhibitors of thymidylate synthetase from bacterial and mammalian sources. Mol Pharmacol 16:261–269, 1979.PubMedGoogle Scholar
  76. 76.
    Jones TR: 5-Substituted quinazoline antifolates. Eur J Cancer 16:707–711, 1980.PubMedGoogle Scholar
  77. 77.
    Calvert AH, Jones TR, Dady PJ, Grzelakowska-Sztabert B, Paine RM, Taylor GA, Harrap KR: Quinazoline antifolates with dual biochemical loci of action. Biochemical and biological studies directed towards overcoming methotrexate resistance. Eur J Cancer 16:713–722, 1980.PubMedGoogle Scholar
  78. 78.
    Jones TR, Calvert AH, Jackman AL, Brown SJ, Harrap KR: 2-Amino-4-hydroxy quinazoline analogues of folic acid as thymidylate synthetase inhibitors. Brit J Cancer 40:318–319, 1979.Google Scholar
  79. 79.
    Calvert AH, Jones TR, Jackman AL, Brown SJ, Harrap KR: An approach to the design of antimetabolites active against cells resistant to conventional agents illustrated by quinazoline antifolates with N10-substitutions. In: Human Cancer, Its Characterization and Treatment, Davis W, Harrap KR, Stathopoulos G (eds). Amsterdam: Excerpta Medica, 1980, pp 272–283.Google Scholar
  80. 80.
    Jones TR, Calvert AH, Jackman AL, Brown SJ, Jones M, Harrap KR: A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in mice. Eur J Cancer 17:11–19, 1981.PubMedGoogle Scholar
  81. 81.
    Jackman AL, Calvert AH, Hart LI, Harrap KR: Inhibition of thymidylate synthetase by the new quinazoline antifolate CB3717; Enzyme purification and kinetics. In: Adv Exptl Med Biol 165B. De Bruyn CHMM, Simmonds HA, Müller MM (Eds): Plenum, pp 375–378, 1984.Google Scholar
  82. 82.
    Piper JR, McCaleb GS, Montgomery JA, Kisliuk RL, Gaumont Y, Sirotnak FM: 10-Propargylaminopterin and alkyl homologues of methotrexate as inhibitors of folate metabolism. J Med Chem 25:877–880, 1982.PubMedGoogle Scholar
  83. 83.
    Jenny E, Greenberg DM: Further studies on thymidylate synthetase from calf thymus. J Biol Chem 238:3378–3382, 1963.PubMedGoogle Scholar
  84. 84.
    Horinishi H, Greenberg DM: Purification and properties of thymidylate synthetase from calf thymus. Biochim Biophys Acta 258:741–752, 1972.PubMedGoogle Scholar
  85. 85.
    Dwivedi CM, Kisliuk RL, Maley GF: Structural studies of calf thymus thymidylate synthetase. In: Chemistry and Biology of Pteridines, Blair JA (ed). Berlin: de Gruyter, 1983, pp 639–644.Google Scholar
  86. 86.
    Whiteley JM, Jerkunica I, Deits T: Thymidylate synthetase from amethopterin-resistant Lactobacillus casei. Purification by affinity chromatography. Biochemistry 13:2044–2050, 1974.PubMedGoogle Scholar
  87. 87.
    Dananberg PV, Langenbach RJ, Heidelberger C: Purification of thymidylate synthetase from L. casei by affinity chromatography. Biochem Biophys Res Comm 49:1029–1033, 1972.Google Scholar
  88. 88.
    Galivan JH, Maley GF, Maley F: The effect of substrate analogs on the circular dichroic spectra of thymidylate synthetase from Lactobacillus casei. Biochemistry 14:3338–3344, 1975.PubMedGoogle Scholar
  89. 89.
    Plante LT, Gaumont Y, Kisliuk RL: Na-[Pteroyltetra(γ-glutamyl)]-lysine as a ligand for the purification of thymidylate synthetase by affinity chromatography. Prep Biochem 8:91–98, 1978.PubMedGoogle Scholar
  90. 90.
    Plante LT: Antifolate inhibitors of thymidylate synthetase as ligands for affinity chromatography. In: Chemistry and Biology of Pteridines, Kisliuk RL, Brown GM (eds). New York: Elsevier/North Holland, 1979, pp 267–271.Google Scholar
  91. 91.
    Fridland A, Langenbach RJ, Heidelberger C: Purification of thymidylate synthetase from Ehrlich ascites carcinoma cells. J Biol Chem 246:7110–7114, 1971.PubMedGoogle Scholar
  92. 92.
    Jastreboff M, Kedzierska B, Rode W: Properties of thymidylate synthetase from Ehrlich ascites carcinoma cells. Biochem Pharmacol 31:217–223, 1982.PubMedGoogle Scholar
  93. 93.
    Jastreboff MM, Kedzierska B, Rode W: Altered thymidylate synthetase in 5-fluorodeox-yuridine-resistant Ehrlich ascites carcinoma cells. Biochem Pharmacol 32:2259–2267, 1983.PubMedGoogle Scholar
  94. 94.
    Capco GR, Krupp JR, Mathews CK: Bacteriophage-coded thymidylate synthetase: Characteristics of the T4 and T5 enzymes. Arch Biochem Biophys 158:726–735, 1973.PubMedGoogle Scholar
  95. 95.
    Galivan J, Maley GF, Maley F: Purification and properties of T2 bacteriophage-induced thymidylate synthetase. Biochemistry 13:2282–2289, 1974.PubMedGoogle Scholar
  96. 96.
    Rode W, Zielińska ZM, Slavik K, Slavíková V: Purification of thymidylate synthetase by means of affinity chromatography on tetrahydroamethopterin-aminoethyl-sepharose. Biochem Soc Trans 4:925–927, 1976.PubMedGoogle Scholar
  97. 97.
    Neuhard J, Price AR, Schack L, Thomassen E: Two thymidylate synthetases in Bacillus subtilis. Proc Natl Acad Sci USA 15:1194–1198, 1978.Google Scholar
  98. 98.
    Belfort M, Maley GF, Maley F: Characterization of the Escherichia coli thyA gene and its amplified thymidylate synthetase product. Proc Natl Acad Sci USA 80:1858–1861, 1983.PubMedGoogle Scholar
  99. 99.
    Rode W, Scanlon KJ, Hynes J, Bertino JR: Purification of mammalian tumour (L1210) thymidylate synthetase by affinity chromatography on stable biospecific absorbent. J Biol Chem 254:11538–11543, 1979.PubMedGoogle Scholar
  100. 100.
    Banerjee CK, Bennett Jr L, Brockman RW, Sani BP, Temple Jr C: A convenient procedure for purification of thymidylate synthetase from L1210 cells. Anal Biochem 121:275–280, 1982.PubMedGoogle Scholar
  101. 101.
    Lockshin A, Moran RG, Danenberg PV: Thymidylate synthetase purified to homogeneity from human leukemic cells. Proc Natl Acad Sci USA 76:750–754, 1979.PubMedGoogle Scholar
  102. 102.
    Bapat AR, Zarow C, Danenberg PV: Human leukemic cells resistant to 5-fluoro-2′-deox-yuridine contain a thymidylate synthetase with lower affinity for nucleotides. J Bio Chem 258:4130–4136, 1983.Google Scholar
  103. 103.
    Rode W, Dolnick BJ, Bertino JR: Isolation of a homogeneous preparation of human thymidylate synthetase from HeLa cells. Biochem Pharmacol 29:723–726, 1980.PubMedGoogle Scholar
  104. 104.
    Priest DG, Doig MT, Hynes JB: Purification of mouse liver thymidylate synthetase by affinity chromatography using 10-methyl-5,8-dideazafolate as the affinant. Experientia 37:119–120, 1981.PubMedGoogle Scholar
  105. 105.
    Belfort M, Moelleken A, Maley GF, Maley F: Purification and properties of T4 phage thymidylate synthetase produced by the cloned gene in an amplification vector. J Biol Chem 258:2045–2051, 1983.PubMedGoogle Scholar
  106. 106.
    Rao KN, Kisliuk RL: Association of RNA with thymidylate synthetase from methotrex-ate-resistant streptococcus faecium. Proc Natl Acad Sci USA 80:916–920, 1983.PubMedGoogle Scholar
  107. 107.
    Leary RP, Kisliuk RL: Crystalline thymidylate synthetase from dichloromethotrexate-resistant Lactobacillus casei. Prep Biochem 1:47–54, 1971.PubMedGoogle Scholar
  108. 108.
    Lyon JA, Pollard AL, Loeble RB, Dunlap RB: Thymidylate synthetase: An improved purification procedure and description of some spectral properties. Cancer Biochem Biophys 1:121–128, 1975.Google Scholar
  109. 109.
    Dunlap RB: TMP synthetase from Lactobacillus casei. Meth Enzymol 51:90–97, 1978.PubMedGoogle Scholar
  110. 110.
    Whiteley JM: 5-Fluoro-2′-deoxyuridylate-agarose in the affinity-chromatographic purification of thymidylate synthetase. Meth Enzymol 51:98–104, 1978.PubMedGoogle Scholar
  111. 111.
    Danenberg PV, Langenbach RJ, Heidelberger C: Structures of reversible and irreversible complexes of thymidylate synthetase and fluorinated pyrimidine nucleotides. Biochemistry 13:926–933, 1974.PubMedGoogle Scholar
  112. 112.
    Belfort M, Maley G, Pedersen-Lane J, Maley F: Primary structure of the Escherichia coli thyA gene and its thymidylate synthetase product. Proc Natl Acad Sci USA 80:4914–4918, 1983.PubMedGoogle Scholar
  113. 113.
    Chabner BA: Pyrimidine antagonists. In: Pharmacologic Principles of Cancer Treatment. Chabner BA (ed) WB Saunders Co, 1982.Google Scholar
  114. 114.
    Harrap KR, Hill BT, Furness ME, Hart LI: Sites of action of amethopterin: Intrinsic and acquired resistance. Ann NY Acad Sci 186:312–324, 1971.PubMedGoogle Scholar
  115. 115.
    Jackson RC, Niethammer D: Acquired methotrexate resistance in lymphoblasts resulting from altered kinetic properties of dihydrofolate reductase. Eur J Cancer 13:567–575, 1977.PubMedGoogle Scholar
  116. 116.
    Rosenblatt, Whitehead VM, Vera N, Pottier A, Dupont M, Vuchich MJ: Prolonged inhibition of DNA synthesis associated with the accummulation of methotrexate polyglutamates by cultured tumour cells. Mol Pharmacol 14:1143–1147, 1978.PubMedGoogle Scholar
  117. 117.
    Whitehead VM: Synthesis of methotrexate polyglutamates in L1 210 murine leukemia cells. Cancer Res 37:408–412, 1977.PubMedGoogle Scholar
  118. 118.
    Schilsky RL, Baily BD, Chabner BA: Methotrexate polyglutamate synthesis by cultured human breast cancer cells. Proc Natl Acad Sci USA 77:2919–2922, 1980.PubMedGoogle Scholar
  119. 119.
    Galivan J: Transport and metabolism of methotrexate in normal and resistant cultured rat hepatoma cells. Cancer Res 39:735–743, 1979.PubMedGoogle Scholar
  120. 120.
    Poser RG, Sirotnak FM, Chello PL: Differential synthesis of methotrexate polyglutamate in normal proliferative and neoplastic mouse tissues in vivo. Cancer Res 41:4441–4446, 1981.PubMedGoogle Scholar
  121. 121.
    Fry DW, Yalowich JC, Goldman ID: Rapid formation of polygamma-glutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by H PLC in the Ehrlich ascites tumour cell in vitro. J Biol Chem 257:1890–1896, 1982.PubMedGoogle Scholar
  122. 122.
    Baugh CM, Krumdieck C, Nair MG: Polygammaglutamyl metabolites of methotrexate. Biochem Biophys Res Comm 52:24–27, 1973.Google Scholar
  123. 123.
    Covey JM: Polyglutamate derivatives of folic acid coenzymes and methotrexate. Life Sciences 26:665–678, 1980.PubMedGoogle Scholar
  124. 124.
    Szeto DW, Cheng Y-C, Rosowsky A, Yu C-S, Modest EJ, Piper JR, Temple Jr C, Elliott RD, Rose JD, Montgomery JA: Human thymidylate synthetase-III effects of methotrexate and folate analogues. Biochem Pharmacol 28:2633–2637, 1979.PubMedGoogle Scholar
  125. 125.
    Bertino JR, McGuire JJ: Folates and cancer chemotherapy. In: Chemistry and Biology of Pteridines. Berlin: de Gruyter, pp 263–274, 1983.Google Scholar
  126. 126.
    Jolivet J, Drake JC, Chabner BA: Inhibition of human thymidylate synthetase (TS) by methotrexate polyglutamates (MTXPGs). Proc AACR 24:276, 1983.Google Scholar
  127. 127.
    Jackson RC, Jackman AL, Calvert AH: Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, CB3717, on human lymphoblastoid cells. Biochem Pharmacol 32:3783–3790, 1983.PubMedGoogle Scholar
  128. 128.
    Tattersall MHN, Jackson RC, Connors TA, Harrap KR: Combination chemotherapy: The interaction of methotrexate and 5-fluorouracil. Europ J Cancer 9:733–739, 1973.Google Scholar
  129. 129.
    Jackson RC: Modulation of methotrexate toxicity by thymidine: sequence dependent biochemical effects. Mol Pharmacol 18:281–286, 1980.PubMedGoogle Scholar
  130. 130.
    Myers CE, Young RC, Chabner BA: Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion. J Clin Invest 56:1231–1238, 1975.PubMedGoogle Scholar
  131. 131.
    Klubes P, Connelly K, Cerna I, Mandel HG: Effects of 5-fluorouracil on 5-fluorodeoxyu-ridine 5′-monophosphate and 2-deoxyuridine 5′-monophosphate pools, and DNA synthesis in solid mouse L1210 and rat Walker 256 tumours. Cancer Res 38:2325–2331, 1978.PubMedGoogle Scholar
  132. 132.
    Ardalan B, Buscaglia MD, Schein PS: Tumour 5-fluorodeoxyuridylate concentration as a determinant of 5-fluorouracil response. Biochem Pharmacol 27:2009–2013, 1978.PubMedGoogle Scholar
  133. 133.
    Maybaum J, Cohen MB, Sadee W: In vivo rates of pyrimidine nucleotide metabolism in intact mouse T-lymphoma (S-49) cells treated with 5-fluorouracil. J Biol Chem 256:2126–2130, 1981.PubMedGoogle Scholar
  134. 134.
    Myers CE: The pharmacology of the fluoropyrimidines. Pharm Revs 33:1–15, 1981.Google Scholar
  135. 135.
    Ardalan B, Cooney D, Macdonald JS: Physiological and pharmacological determinants of sensitivity and resistance to 5-fluorouracil in lower animals and man. Adv in Pharmacol and Chem 17:289–321, 1980.Google Scholar
  136. 136.
    Sawyer RC, Stolfi RL, Nayak R, Martin DS: Mechanism of cytotoxicity of 5-fluorouracil chemotherapy of two murine solid tumours. In: Nucleosides and Cancer Treatment. Australia: Academic Press, pp 309–337, 1981.Google Scholar
  137. 137.
    Kufe DW, Major PP: 5-fluorouracil incorporation into human breast carcinoma RNA correlates with cytotoxicity. J Biol Chem 256:9802–9805, 1981.PubMedGoogle Scholar
  138. 138.
    Hadjiolova KV, Naydenova ZG, Hadjiolov AA: Inhibition of ribosomal RNA maturation in Friend erythroleukemia cells by 5-fluorouridine and toyocamycin. Biochem Pharmacol 30:1861–1863, 1981.PubMedGoogle Scholar
  139. 139.
    Wilkinson DS, Cihak A, Pitot HC: Inhibition of ribosomal ribonucleic acid maturation in rat liver by 5-fluoroorotic acid resulting in the selective labelling of cytoplasmic messenger ribonucleic acid. J Biol Chem 246:6418–6427, 1971.PubMedGoogle Scholar
  140. 140.
    Wilkinson DS, 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
  141. 141.
    Carrico CK, Glazer RI: Effects of 5-fluorouracil on the synthesis and translation of polyad-enylic acid-containint RNA from regenerating rat liver. Cancer Res 39:3694–3701, 1979.PubMedGoogle Scholar
  142. 142.
    Danenberg PV, Heidelberger C, Mulkins MA, Peterson AR: The incorporation of 5-fluoro-2’-deoxyuridine into DNA of mammalian tumour cells. Biochem Biophys Res Comm 102:654–658, 1981.PubMedGoogle Scholar
  143. 143.
    Kufe DW, Major PP, Egan EM, Loh E: 5-Fluoro-2′,-deoxyuridine incorporation in L1210 DNA. J Biol Chem 256:8885–8888, 1981.PubMedGoogle Scholar
  144. 144.
    Caradonna SJ, Cheng Y-c: The role of deoxyuridine triphosphate nucleotidohydrolase, uracil-DNA glycosylase, and DNA polymerase alpha in the metabolism of FUdR in human tumour cells. Mol Pharmacol 18:513–520, 1980.PubMedGoogle Scholar
  145. 145.
    Major PP, Egan E, Herrick D, Kufe DW: 5-fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Res 42:3005–3009, 1982.PubMedGoogle Scholar
  146. 146.
    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 polymerases alpha and beta from calf thymus. Cancer Res 41:4132–4135, 1981.PubMedGoogle Scholar
  147. 147.
    Laskin JD, Evans RM, Slocum HK, Burke D, Hakala MT: Basis for natural variation in sensitivity to 5-fluorouracil in mouse and human cells in culture. Cancer Res 39:383–390, 1979.PubMedGoogle Scholar
  148. 148.
    Houghton JA, Houghton PJ, Wooten RS: Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine and 5-fluoro-2′-deoxyuridine. Cancer Res 39:2406–1423, 1979.PubMedGoogle Scholar
  149. 149.
    Piper AA, Fox RM: Differential metabolism of fluorouracil (FU) in cultured human T and B lymphocyte cell lines: modulation of sensitivity by purine nucleosides and bases. In: Nucleosides and Cancer Treatment. Australia: Academic Press, 1981, pp 251–265.Google Scholar
  150. 150.
    Houghton JA, Houghton PJ: Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma. Eur J Cancer 19:807–815, 1983.Google Scholar
  151. 151.
    Spiegelman S, Nayak R, Sawyer R, Stolfi R, Martin D: Potentiation of the antitumour activity of 5-FU by thymidine and its correlation with the formation of (5FU) RNA. Cancer 45:1129–1134, 1980.PubMedGoogle Scholar
  152. 152.
    Evans RM, Laskin JD, Hakala MT: Assessment of growth-limiting events caused by 5-fluorouracil in mouse cells and human cells. Cancer Res 40:4113–4122, 1980.PubMedGoogle Scholar
  153. 153.
    Maybaum J, Ullman B, Mandel HG, Day JL, Sadee W: Regulation of RNA- and DNA-directed actions of 5-fluoropyrimidines in mouse T-lymphoma (S-49) cells. Cancer Res 40:4209–4215, 1980.PubMedGoogle Scholar
  154. 154.
    Chabner BA: Antimetabolites. In: Cancer Chemotherapy: The EORTC Cancer Chemotherapy Annual 2. Pinedo HM (ed) Excerpta Medica, 1980, pp 1–26.Google Scholar
  155. 155.
    Jackman AL, Calvert AH, Taylor GA, Harrap KR: Biological properties of the new quinazoline inhibitor of thymidylate synthetase, CB3717. In: The Control of Tumour Growth and its Biological Bases. Davis W, Maltoni C, Tanneberger St (eds). Berlin: Akademie-Verlag, 1983, pp 404–410.Google Scholar
  156. 156.
    Taylor GA, Jackman AL, Calvert AH, Harrap KR: Plasma nucleoside and base levels following treatment with the new thymidylate synthetase inhibitor, CB3717. In: Adv Exptl Med Biol 165B. De Bruyn CHMM, Simmonds HA, Müller MM (Eds): Plenum, pp 379–382, 1984.Google Scholar
  157. 157.
    Jackman AL, Taylor GA, Calvert AH, Newell DR, Harrap KR: Biochemical disturbances observed in vitro and in vivo following inhibition of thymidylate synthetase by CB3717. Brit J Cancer 46:505–506, 1982.Google Scholar
  158. 158.
    Calvert AH, Jackman AL, Alison DL, Siddik ZH, Newell DR, Newlands ES, Taylor GA, Harrap KR: Clinical and experimental studies with a folate based inhibitor of thymidylate synthetase. Proc 13th Int Cancer Congress, Seattle (1983) in press.Google Scholar
  159. 159.
    Calvert AH, Alison DL, Harland SJ, Jackman AL, Mooney CJ, Smith IE, Harrap KR: Phase I studies with CB3717. Brit J cancer 48:116–117, 1983.Google Scholar
  160. 160.
    Alison DL, Calvert AH: Early clinical studies with CB3717 at the Royal Marsden Hospital. In: Cancer Chemotherapy and Selective Drug Development. Harrap KR, Davis W, Calvert AH (Eds): Martinus Nijhoff, p 535, 1984.Google Scholar
  161. 161.
    Newell DR, Siddik ZH, Calvert AH, Jackman AL, Alison DL, McGhee KG, Harrap KR: Pharmacokinetic and toxicity studies with CB3717. Proc Am Assoc Cancer Res 23:181, 1982.Google Scholar
  162. 162.
    Fernandes DJ, Bertino JR, Hynes JB: Biochemical and antitumour effects of 5,8-dideazai-sopteroylglutamate, a unique quinazoline inhibitor of thymidylate synthetase. Cancer Res 43:1117–1123, 1983.PubMedGoogle Scholar
  163. 163.
    Jackson RC: Int J Bio-Med Comput 11:197, 1980.Google Scholar
  164. 164.
    Tattersall MHN, Jackson RC, Jackson STM, Harrap KR: Factors determining cell sensitivity to methotrexate: studies of folate and deoxyribonucleoside triphosphate pools in five mammalian cell lines. Europ J Cancer 10:819–826, 1974.Google Scholar
  165. 165.
    Chang C-H, Cheng Y-C: Effects of nucleoside triphosphates on human ribonucleoside reductase from Molt-4F cells. Cancer Res 39:5087–5092, 1979.PubMedGoogle Scholar
  166. 166.
    Moore EC, Hulbert RB: J Biol Chem 24:4802, 1966.Google Scholar
  167. 167.
    Diddens K, Niethammer D, Jackson RC: Human cells resistant to methotrexate: cross resistance and collateral sensitivity to the non-classical antifolates trimetrexate, metoprine, homofolic acid and CB3717. In: Chemistry and Biology of Pteridines, Blair JA (ed). Berlin/New York: deGruyter, 1983, pp 953–957.Google Scholar
  168. 168.
    Jackman AL, Alison DL, Calvert AH, Harrap KR: Increased thymidylate synthetase activity in L1210 cells resistant to CB3717. Brit J Cancer 48:133–134, 1983.Google Scholar
  169. 169.
    Spector T, Cleland WW: Meanings of Ki for conventional and alternate-substrate inhibitors. Biochem Pharmacol 30:1–7, 1981.PubMedGoogle Scholar
  170. 170.
    Christopherson RI, Dugglegy RG: Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate. Europ J Biochem 134:331–335, 1983.PubMedGoogle Scholar
  171. 171.
    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
  172. 172.
    Moran RG, Danenberg PV, Heidelberger C: Therapeutic response of leukemic mice treated with fluorinated pyrimidines and inhibitors of deoxyuridylate synthesis. Biochem Pharmacol 31:2929–2935, 1982.PubMedGoogle Scholar
  173. 173.
    Houghton JA, Schmidt C, Houghton PJ: The effect of derivatives of folic acid on the fluorodeoxyuridylate thymidylate synthetase covalent complex in human colon xenografts. Europ J Cancer Clin Oncol 18:347–354, 1982.PubMedGoogle Scholar
  174. 174.
    Moran RG, Werkheiser WC, Zakrzewski SF: Folate metabolism in mammalian cells in culture. J Biol Chem 251:3569–3575, 1976.PubMedGoogle Scholar
  175. 175.
    Jackson RC, Harrap KR: Studies with a mathematical model of folate metabolism. Arch Biochem Biophys 158:827–841, 1973.PubMedGoogle Scholar
  176. 176.
    Chabner BA: Methotrexate. In: Pharmacologic Principles in Cancer Treatment. Chabner BA (ed). USA: WB Saunders CO, 1982, pp 229–255.Google Scholar
  177. 177.
    Houghton JA, Maroda SJ, Phillips JO, Houghton PJ: Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice. Cancer Res 41:144–149, 1981.PubMedGoogle Scholar
  178. 178.
    Washtien WL: Thymidylate synthetase levels as a factor in 5-fluorodeoxyuridine and methotrexate cytotoxicity in gastrointestinal tumour cells. Mol Pharmacol 21:723–728, 1982.PubMedGoogle Scholar
  179. 179.
    Dolnick BJ, Cheng Y: Human Thymidylate synthetase II. derivatives of pteroylmono-and-polyglutamates as substrates and inhibitors. J Biol Chem 253:3563–3567, 1978.PubMedGoogle Scholar
  180. 180.
    Clendeninn NJ, Cowan KH, Kaufman BT, Nadkarni MV, Chabner BA: Dihydrofolate reductase (DHFR) from a methotrexate resistant human breast cancer cell line: purification, properties and binding of methotrexte (MTX) and polyglutamates. Proc Am Assoc Cancer Res 24:276, 1983.Google Scholar
  181. 181.
    Huennekens FM, Suresh MR, Grimshaw CE, Jacobsen DW, Quadros Et, Vitols KS, Henderson GB: Transport of folate and pterin compounds. In: Chemistry and Biology of Pteridines Blaie JA (ed). Berlin/New York: deGruyter, 1983, pp 1–22.Google Scholar
  182. 182.
    Jackman AL, Alison DL, Calvert AH, Barrie SE, Harrap KR: Studies with mutant L1210 cell lines that have acquired resistance to CB3717. In: Cancer Chemotherapy and Selective Drug Development. Harrap KR, Davis W, Calvert AH (Eds): Martinus Nijhoff, p 527, 1984.Google Scholar
  183. 183.
    Plagemann PGW, Erbe J: The deoxyribonucleoside transport systems of cultured Novikiff rat hepatoma cells. J Cell Physiol 83:337–344, 1974.PubMedGoogle Scholar
  184. 184.
    Leyva A, Nederbragt H, Lankelma J, Pinedo HM: Methotrexate cytotoxicity: Studies on its reversal by folates and nucleosides. Cancer Treat Rep 65:45–54, 1981.PubMedGoogle Scholar
  185. 185.
    Jackman AL, Taylor GA, Calvert AH, Harrap KR: Modulation of Anti-Metabolite effects. Biochem Pharmacot 33:3269–3275, 1984.Google Scholar
  186. 186.
    Goulian M, Bleue B, Tseng BY: The effect of methotrexate on levels of dUTP in animal cells. J Biol Chem 255:10630–10637, 1980.PubMedGoogle Scholar
  187. 187.
    Sedwick WD, Kutler M, Brown OE: Antifolate-induced misincorporation of deoxyuridine monophosphate into DNA: Inhibition of high molecular weight DNA synthesis in human lymphoblastoid cells. Proc Natl Acad Sci USA 78:917–921, 1981.PubMedGoogle Scholar
  188. 188.
    Goulian M, Bleue B, Tseng BY: Methotrexate-induced incorporation of uracil into DNA. Proc Natl Acad Sci USA 77:1956–1960, 1980.PubMedGoogle Scholar
  189. 189.
    Dube DK, Kunkel TA, Seal G, Loeb LA: Distinctive properties of mammalian DNA polymerases. Biochim Biophys Acta 561:369–382, 1979.PubMedGoogle Scholar
  190. 190.
    Bestwick RK, Moffet DGL, Sipiro C, Mathews CK: Differential effects of methotrexate or fluorodeoxyuridine upon mitochondrial and cellular nucleotide pools. In: Chemistry and Biology of Pteridines, Blair JA (ed). Berlin/New York: deGruyter, 1983, pp 311–315.Google Scholar
  191. 191.
    Peterson MS, Ingraham HA, Goulian M: 2′-deoxyribosyl analogues of UDP-n-acetylglucosamine in cells treated with methotrexate or 5-fluorodeoxyuridine. J Biol Chem 258:10831–10834, 1983.PubMedGoogle Scholar
  192. 192.
    Bertino JR: Towards improved selectivity in cancer chemotherapy: The Richard and Hilda Rosenthal Foundation Award Lecture. Cancer Res 39:293–304, 1979.PubMedGoogle Scholar
  193. 193.
    Jolivet J, Curt GA, Clendeninn NS, Chabner BA: Antimetabolites. In: Cancer Chemotherapy: The EORTC Cancer Chemotherapy Annual 4, Pinedo HM (ed), 1982, pp 1–28.Google Scholar
  194. 194.
    Dower WJ, Schimke RT: Human dihydrofolate reductase (DHFR) gene amplification after (MTX) treatment. Proc Am Ass Cancer Res 24:280, 1983.Google Scholar
  195. 195.
    Reichard P, Skold O, Klein G, Revesz I, Magnussom P-H: Studies on resistance against 5-fluorouracil. Cancer Res 22:235–243, 1962.PubMedGoogle Scholar
  196. 196.
    Kasbekar DK, Greenberg DM: Studies on tumour resistance to 5-fluorouracil. Cancer Res 23:818–824, 1963.PubMedGoogle Scholar
  197. 197.
    Reyes P, Hall TC: Synthesis of 5-fluorouridine 5′-phosphate by a pyrimidine phosphori-bosyltransferase of mammalian origin-II. Correlation between the tumour levels of the enzyme and the 5-fluorouracil-promoted increase in survival of tumour-bearing mice. Biochem Pharmacol 18:2587–2590, 1969.PubMedGoogle Scholar
  198. 198.
    Umeda M, Heidelberger C: Comparative studies of fluorinated pyrimidines with various cell lines. Cancer Res 28:2529–2538, 1968.PubMedGoogle Scholar
  199. 199.
    Priest DG, Ledford BE: Increased TS in 5-fluorodeoxyuridine resistant cultured hepatoma cells. Biochem Pharmacol 29:1549–1553, 1980.PubMedGoogle Scholar
  200. 200.
    Baskin F, Carlin SC, Kraus P, Friedkin M, Rosenberg RN: Experimental chemotherapy of mouse neuroblastoma. Mol Pharmacol 11:105–117, 1975.PubMedGoogle Scholar
  201. 201.
    Kufe DW, Scott P, Fram R, Major P: Biologic effects of 5-fluoro-2′,-deoxyuridine incorporation in L1210 deoxyribonucleic acid. Biochem Pharmacol 32:1337–1340, 1983.PubMedGoogle Scholar
  202. 202.
    Cheng YC, Nakayama K: Effects of 5-fluoro-2′-deoxyuridine on DNA metabolism in HeLa cells. Mol Pharmacol 23:171–174, 1983.PubMedGoogle Scholar
  203. 203.
    Ingraham HA, Tseng BY, Goulian M: Nucleotide levels and incorporation of 5-fluourou-racil and uracil into DNA of cells treated with 5-fluorodeoxyuridine. Mol Pharmacol 21:211–216, 1982.PubMedGoogle Scholar
  204. 204.
    Cohen JL, Irwin LE, Marchai GJ, Darvey H, Bateman JR: Clinical pharmacology of oral and intravenous 5-fluorouracil. Cancer Chemother Rep part 1 58:723–731, 1974.Google Scholar
  205. 205.
    Sitar DS, Shaw DH, Thirlwell MP, Ruedy JR: Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation. Cancer Res 37:3981–3984, 1977.PubMedGoogle Scholar
  206. 206.
    McMillan WE, Wolberg WH, Welling PG: Pharmacokinetics of fluorouracil in humans. Cancer Res 38:3479–3482, 1978.Google Scholar
  207. 207.
    Kirkwood JM, Ensminger W, Rosowsky a, Papthanasopoulos n, Frei E III: Comparison of pharmacokinetics of 5-fluorouracil with concurrent thymidine infusion in a phase I trial. Cancer Res 40:107–113, 1980.PubMedGoogle Scholar
  208. 208.
    Garrett ER, Hurst GH, Green RJ: Kinetics and mechanisms of drug action on microorganisms XXIII. Microbial kinetic assay for fluorouracil in biological fluids and its application to human pharmacokinetics. J Pharm Sci 66:1422–1429, 1977.PubMedGoogle Scholar
  209. 209.
    Finch RE, Bending MR, Lant AF: Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. Brit J Clin Pharmacol 7:613–614, 1979.Google Scholar
  210. 210.
    McDermott BJ, Van den Berg HW, Murphey RF: Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. Cancer Chemother Pharmacol 9:173–178, 1982.PubMedGoogle Scholar
  211. 211.
    Finn C, Sadee W: Determination of 5-fluorouracil (NSC 19893) plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemother Rep 59:279–286, 1975.Google Scholar
  212. 212.
    Alison DL, Newell DR, Calvert AH: Pharmacokinetic studies in humans with CB3717 (N-(4-(2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino)benzoyl)-L-glutamic acid. Brit J Cancer 48:126, 1983.Google Scholar
  213. 213.
    Howell SB, Mansfield SJ, Taetle R: Significance of variation in serum concentration for the marrow toxicity of MTX. Cancer Chemother Pharmacol 5:221–226, 1981.PubMedGoogle Scholar
  214. 214.
    Kish J, Drelichman A, Jacobs J, Hoschner J, Kinzie J, Loh J, Weaver A, Al Sarraf M: Clinical trial of cisplatin and 5-FU as initial treatment for advanced squamous carcinoma of the head and neck. Cancer Treat Rep 66:471–474, 1982.PubMedGoogle Scholar
  215. 215.
    Qhnuma T, Roboz J, Waxman S, Mandel E, Martin DS, Holland JF: Clinical pharmacologic effects of thymidine and 5-FU. Cancer Treat Rep 64:1169–1177, 1980.Google Scholar
  216. 216.
    Woodcock TM, Martin DS, Damin LAM, Kerneny NE, Young CW: Combination clinical trials with thymidine and fluorouracil: A phase I and clinical pharmacologic examination. Cancer 45:1135–1143, 1980.PubMedGoogle Scholar
  217. 217.
    Au JLS, Rustum YM, Ledesma EJ, Mittleman A, Creaven PJ: Clinical pharmacological studies of concurrent infusion of 5-fluorouracil and thymidine in the treatment of colorectal carcinomas. Cancer Res 42:2930–2937, 1982.PubMedGoogle Scholar
  218. 218.
    Fernandes DJ, Bertino JR: 5-Fluorouracil-methotrexate synergy: enhancement of 5-fluorodeoxyuridylate binding to thymidylate synthetase by dihydropteroylpolyglutamates. Proc Natl Acad Sci USA 77:5563–5667, 1980.Google Scholar
  219. 219.
    Cadman EC, Heimer R, Davis L: Enhanced 5-fluorouracil formation after methotrexate administration: explanation for drug synergism. Science 250:1135–1137, 1979.Google Scholar
  220. 220.
    Lajthe LG, Vane JR: Dependence of bone marrow cells on the liver for purine supply. Nature 182:191–192, 1958.Google Scholar
  221. 221.
    Tisman G, WU SJG: Effectiveness of intermediate-dose methotrexate and high dose 5-fluorouracil as sequential combination chemotherapy in refractory breast cancer and as primary therapy in metastatic adenocarcinoma of the colon. Cancer Treat Rep 64:829–835, 1980.PubMedGoogle Scholar
  222. 222.
    Gerwitz AM, Cadman E: Preliminary report on the efficacy of sequential methotrexate and 5-fluorouracil in advanced breast cancer. Cancer 47:2552–2555, 1981.Google Scholar
  223. 223.
    Ringborg U, Evert G, Kinnman J, Landquist PG, Strander H: Sequential methotrexate-5-fluorouracil treatment of squamous cell carcinoma of the head and neck. Cancer 1983, (in press).Google Scholar
  224. 224.
    Pitman SW, Kowal DC, Papac RJ, Bertino JR: Sequential methotrexate-5-fluorouracil. A highly active drug combination in advanced squamous cell carcinoma of the head and neck. Proc Am Assoc Cancer Res 21:607, 1980.Google Scholar
  225. 225.
    Wienerman B, Schacter B, Schipper H, Bowman D, Levitt M: Sequential methotrexate and 5FU in the treatment of colorectal cancer. Cancer Treat Rep 66:1553–1555, 1982.Google Scholar
  226. 226.
    Cantrell JE, Brunet R, Lagarde C, Schein PS, Smith FP: Phase II study of sequential methotrexate-5FU therapy in advanced measurable colorectal cancer. Cancer Treat Rep 66:1563–1565, 1982.PubMedGoogle Scholar
  227. 227.
    Bertino JR: Clinical application of the scheduled combination of methotrexate and 5-fluorouracil. In: The Chemotherapy of Breast, Gastrointestinal and Head and Neck Cancer. Current Status and Potential Role of Methotrexate and 5-Fluorouracil. Bertino JR (ed), USA: Pharma Libri, 1983.Google Scholar
  228. 228.
    Browman GP, Archibald SD, Young JEM, Hryniuk WM, Russell R, Kiehl K, Levine MN: Prospective randomised trial I hour sequential versus simultaneous methotrexate plus 5-fluorouracil in advanced and recurrent squamous cell head and neck cancer. J Clin Oncol 1983, in press.Google Scholar
  229. 229.
    Coates et al.: J Clin Oncol, 1983, in press.Google Scholar
  230. 230.
    Tattersall MHN: Antimetabolite combinations possessing enhanced efficacy. In: Cancer Chemotherapy and Selective Drug Development. Harrap KR, Davis W, Calvert AH (Eds): Martinus Nijhoff, p 19–32, 1984.Google Scholar
  231. 231.
    Heidelberger C, Kalder G, Mukherjee KI: Studies on fluorinated pyrimidines XL In vitro studies on tumour resistance. Cancer Res 202:903–909, 1960.Google Scholar
  232. 232.
    Machover D, Schwarzenberg L, Goldschmidt E, Tourani JM, Michalski B, Hayat M, Dorval T, Misset JL, Jasmin C, Maral R, Mathe G: Treatment of advanced colorectal and gastric adenocarcinoma with 5-FU combined with high does folinic acid: a pilot study. Cancer Treat Rep 66:1803–1807, 1982.PubMedGoogle Scholar
  233. 233.
    Gilman AG, Goodman LS, Gilman A. (eds): The Pharmacologic Basis of Therapeutics. New York: Macmillan Publishing Co. Inc., 1980, pp 1278–1280.Google Scholar
  234. 234.
    Patt YZ, Chuang VP, Wallace S, Benjamin RS, Fuqua R, Mauligit GM: Hepatic arterial chemotherapy and occlusion for palliation of primary hepatocellular and unknown neoplasm in the liver. Cancer 51:1359–1363, 1983.PubMedGoogle Scholar
  235. 235.
    Oberfield RA, McCaffrey JA, Polio J, Clouse ME, Hamilton TH: Prolonged and continuous percutaneous intra-arterial hepatic infusion chemotherapy in advanced metastatic liver adenocarconoma for colorectal primary. Cancer 44:414–423, 1979.PubMedGoogle Scholar
  236. 236.
    Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, Come S, Steele G, Frei E III: A clinical pharmacological evaluation of hepatic arterial indusions of 5-fluoro-2′-deoxyru-ridine and 5-fluorouracil. Cancer Res 38:3784–3792, 1979.Google Scholar
  237. 237.
    Reed ML, Vaitkevicius VK, Al-Sarraf M, Vaughan CB, Singhakowinta A, Sexon-Parte M, Izbicki R, Baker L, Stratsma GW: The practicality of chronic hepatic artery infusion therapy of primary and metastatic hepatic malignancies. Cancer 47:402–409, 1981.PubMedGoogle Scholar
  238. 238.
    Alison DL, Mooney CJ, Robinson B, Smith IE, Wiltshaw E, McElwain TJ, Calvert AH: Phase I clinical trial of CB3717 ((N-(4-(N-((2-amino-4-hydroxy-6-quinazolinyl)me-thyl)prop-2-ynylamino)benzoyl)-L-glutamic acid). Proc 4th NCI-EORTC Symp on New Drugs in cancer Therapy 1983, in press.Google Scholar
  239. 239.
    Straw JA, Talbot DC, Taylor GA, Harrap KR: Some observations on the reversibility of methotrexate toxicity in normal proliferating tissues. J Natl Cancer Inst 58:91–97, 1977.PubMedGoogle Scholar
  240. 240.
    Ensminger WD, Frei E III: The prevention of methotrexate toxicity by thymidine infusions in humans. Cancer Res 37:1857–1863, 1977.PubMedGoogle Scholar
  241. 241.
    Dady PJ, Taylor GA, Muindi JFR, Calvert AH, Smith IE, Smyth JF, Harrap KR: Methotrexate with thymidine, inosine and allopurinol rescue: A phase I clinical study. Cancer Treat Rep 65:37–43, 1981.PubMedGoogle Scholar
  242. 242.
    Pinedo HM, Zaharko DS, Bull JM, Chabner BA: The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides. Cancer Res 36:4418–4478, 1976.PubMedGoogle Scholar
  243. 243.
    Nair MG, Salter DC, Kisliuk RL, Gaumont Y, North G, Sirotnak FM: Folate analogues. 21. Synthesis and antifolate and antitumour activities of N10-(cyanomethyl)-5,8-dideaza-folic acid. J Med Chem 26:605–607, 1983.PubMedGoogle Scholar
  244. 244.
    Goldie JH, Price LA, Harrap KR: Methotrexate toxicity: Correlation with duration of administration, plasma levels, dose and excretion pattern. Europ J Cancer 8:409–414, 1972.Google Scholar

Copyright information

© Martinus Nijhoff Publishers, Boston 1985

Authors and Affiliations

  • Ann L. Jackman
  • Terence R. Jones
  • A. Hilary Calvert

There are no affiliations available

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