Investigational New Drugs

, Volume 24, Issue 1, pp 37–77 | Cite as

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

Article

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Shih C, Thornton D: Preclinical pharmacology studies and the clinical development of a novel multitargeted antifolate, MTA (LY231514). In: Jackman AL (ed) Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 183–201Google Scholar
  2. 2.
    Roy K, Egan MG, Sirlin S, Sirotnak FM: Posttranscriptionally mediated decreases in folylpolyglutamate synthetase gene expression in some folate analogue-resistant variants of the L1210 cell. Evidence for an altered cognate mRNA in the variants affecting the rate of de novo synthesis of the enzyme. J Biol Chem 272(11):6903–6908, 1997PubMedCrossRefGoogle Scholar
  3. 3.
    Sirotnak FM, DeGraw JI, Colwell WT, Piper JR. A new analogue of 10-deazaaminopterin with markedly enhanced curative effects against human tumor xenografts in mice. Cancer Chemother Pharmacol 42:313–318, 1998PubMedCrossRefGoogle Scholar
  4. 4.
    Jackman AL, Newell DR, Gibson W, Jodrell DI, Taylor GA, Bishop JA, Hughes LR, Calvert AH: The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583). Biochem Pharmacol 42(10):1885–1895, 1991PubMedCrossRefGoogle Scholar
  5. 5.
    Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR: ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: A new agent for clinical study. Cancer Res 51:5579–5586, 1991PubMedGoogle Scholar
  6. 6.
    Mendelsohn LG, Worzalla J, Walling J: Preclinical and clinical evaluation of the glycinamide ribonucleotide formyltransferase inhibitors lometrexol and LY3099887. In: Jackman AL (ed) Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Human Press, 1999, pp. 261–280Google Scholar
  7. 7.
    Boritzki T, Zhang C, Bartlett CA, Jackson RC: AG2034. A GARFT inhibitor with selective cytotoxicity to cells that lack a G1checkpoint. In: Jackman AL (ed) Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 281–292Google Scholar
  8. 8.
    Farber S, Diamond LK, Mercer RD, Sylvester RF Jr, Wolff JA: Temporary remissions in acute leukemia in children produced by the folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787–793, 194Google Scholar
  9. 9.
    Hertz R, Li MC, Spencer DB: Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med 93(2):361–366, 1956PubMedGoogle Scholar
  10. 10.
    Li MC, Hertz R, Spence DB: Effect of methotrexate therapy on choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med 93:Abstract 361, 1956PubMedGoogle Scholar
  11. 11.
    Hertz R, Lewis JL Jr., Lipsett MB: Five years experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic disease. Abstract. Gynecol Oncol 23:111, 1986Google Scholar
  12. 12.
    Allegra CJ: In: Chabner BA, Collins JM (eds) Antifolates in Cancer Chemotherapy Principles and Practice. Lippincott, 1990, pp. 110–152Google Scholar
  13. 13.
    Kamen B: Folate and Antifolate pharmacology. Semin Oncol 24: S18–S30, 1997PubMedGoogle Scholar
  14. 14.
    Huennekens FM: The methotrexate story: A paradigm for development of cancer chemotherapeutic agents. Adv Enzyme Regul 34:397–419, 1994PubMedCrossRefGoogle Scholar
  15. 15.
    Stone SR, Morrison JF: Mechanism of inhibition of dihydrofolate reductases from bacterial and vertebrate sources by various classes of folate analogues. Biochim Biophys Acta 869:275–285, 1986PubMedGoogle Scholar
  16. 16.
    White CJ, Loftfield S, Goldman ID: The mechanism of action of MTX III. Requirement of free intracellular methotrexate for maximal suppression of 14C formate incorporation into nucleic acids and protein. Mol Pharmacol 11:287–297, 1975Google Scholar
  17. 17.
    Matthews DA, Bolin JT, Burridge JM, Filman DJ, Volz KW, Kraut J: Dihydrofolate reductase—The stereochemistry of inhibitor selectivity. J Biol Chem 260:392–399, 1985PubMedGoogle Scholar
  18. 18.
    Bertino JR, Donohue DM, Simmons B, Gabrio BW, Silber R, Huennekens FM: The induction of dihydrofolate reductase in leukocytes and erythrocytes of patients treated with methotrexate. J Clin Invest 42:466–475, 1963CrossRefPubMedGoogle Scholar
  19. 19.
    Hillcoat BL, Swett V, Bertino JR: Increase of dihydrofolate reductase activity in cultured mammalian cells after exposure to methotrexate. Proc Natl Acad Sci 58:1632–1637, 1967PubMedCrossRefGoogle Scholar
  20. 20.
    Matherly LH, Angeles SM: Role of N glycosylation in the structure andfunction of themethotrexate transporterfrom CCRF-CEM human lymphoblastic cells. Biochem Pharmacol 47:1094–1098, 1994PubMedCrossRefGoogle Scholar
  21. 21.
    Matherly LH: Molecular and cellular biology of the human reduced folate carrier. Prog Nucleic Acid Res Mol Biol 67:131–132, 2001PubMedCrossRefGoogle Scholar
  22. 22.
    Jansen G: Receptor and carrier mediated transport systems for folates and antifolates. Exploitation for folatebased chemotherapy and immunotherapy. In: Jackman AL (ed) Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 183–201Google Scholar
  23. 23.
    Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH: Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport deficient methotrexate resistant human breast cancer cells. Cancer Res 55:3790–3794, 1995PubMedGoogle Scholar
  24. 24.
    Anderson RG, Kamen BA, Rothberg KG, Lacey SW: Potocytosis: Sequestration and transport of small molecules by caveolae. Science 255:410–411, 1992PubMedCrossRefGoogle Scholar
  25. 25.
    Anderson RG: Caveolae: Where incoming and outgoing messages meet. Proc Natl Acad Sci 90:10909–10913, 1993PubMedCrossRefGoogle Scholar
  26. 26.
    Parton RG, Simons K: Digging into caveolae. Science 269:1398–1999, 1995PubMedCrossRefGoogle Scholar
  27. 27.
    Ragoussis J, Senger G, Trowsdale J, Campbell IG: Genomic organization of the human folate receptor genes on chromosome 11q13. Genomics 14:423–430, 1992PubMedCrossRefGoogle Scholar
  28. 28.
    Ross JF, Chaudhuri PK, Ratnam M: Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Cancer Res 73:2432–2434, 1994Google Scholar
  29. 29.
    Ratnam M, Marquardt H, Duhring JL, Freisheim JH: Homologous membrane folate binding protein in human placenta: Cloning and sequencing of a cDNA. Biochemistry 28:8249–8254, 1989PubMedCrossRefGoogle Scholar
  30. 30.
    Brigle KE, Spinella MJ, Westin EH, Goldman ID: Increased expression and characterization of two distinct folate binding proteins in murine erythroleukemia cells. Biochem Pharmacol 47:337–345, 1994PubMedCrossRefGoogle Scholar
  31. 31.
    Vu T, Amin J, Ramos M, Vanyo L, Tisman G: Cancer patients are frequently in negative vitamin B12 balance and exhibit homocysteinemia. Abstract. Clin Res 39: 667, 1991Google Scholar
  32. 32.
    Spinella MJ, Brigle KE, Sierra EE, Goldman ID: Distinguishing between folate mediated transport and reduced folate carrier mediated transport in L1210 leukemia cell. J Biol Chem 270:7842–7849, 1995PubMedCrossRefGoogle Scholar
  33. 33.
    Assaraf YG, Goldman ID: Loss of folic acid exported function with markedly augmented folate accumulation in lipophilic antifolate-resistant mammalian cells. J Biol Chem 272:17460–17466, 1997PubMedCrossRefGoogle Scholar
  34. 34.
    Mcguire JJ, Hsieh P, Coward JK, Bertino JR: Enzymatic synthesis of folylpolyglutamates. Characterization of the reaction and its products. J Biol Chem 255:5776–5788, 1980PubMedGoogle Scholar
  35. 35.
    Yao R, Schneider E, Ryan TJ, Galivan J: Human gamma-glutamyl hydrolase: Cloning and characterization of the enzyme expressed in vitro. Proc Natl Acad Sci USA 93:10134–10138, 1996PubMedCrossRefGoogle Scholar
  36. 36.
    Bertino JR, Goker E, Gorlick R, Li WW, Banerjee D: Resistance mechanisms to methotrexate in tumors. Stem Cells 14:5–9, 1996PubMedCrossRefGoogle Scholar
  37. 37.
    Kinsella AR, Smith D: Tumor resistance to antimetabolites. Gen Pharmacol 30:623–626, 1998PubMedCrossRefGoogle Scholar
  38. 38.
    Spears CP: Clinical resistance to antimetabolites. Hematology/oncology clinics of North America 9:397–413, 1995PubMedGoogle Scholar
  39. 39.
    Mcguire J: Antifolate polyglutamylation in preclinical and clinical antifolate resistance. In: edited Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 339–363Google Scholar
  40. 40.
    Li WW, Lin JT, Tong WP, Trippett TM, Brennan MF, Bertino JR: Mechanisms of natural resistance to antifolates in human soft tissue sarcomas. Cancer Res 52:1434–1438, 1992PubMedGoogle Scholar
  41. 41.
    Whitehead VM, Vuchich MJ, Lauer SJ, Mahoney D, Carroll AJ, Shuster JJ, Esseltine DW, Payment C, Look AT, Akabutu J, Bowen T, Taylor LD, Camitta B, Pullen DJ: Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (>50 chromosomes) B lineage acute lymphoblastic leukemia: A Pediatric Oncology Group Study. Blood 80:1316–1323, 1992PubMedGoogle Scholar
  42. 42.
    Gorlick R, Guo W, Healey JH, Meyers PA, Ladanyi M, Huvos AG, Bertino JR: Decreased reduced folate carrier (RFC) expression as a mechanism of intrinsic methotrexate (MTX) resistance in osteosarcoma. Abstract. Proc Am Assoc Cancer Res 40:4457, 1999Google Scholar
  43. 43.
    Trippett T, Schlemmer S, Elisseyeff Y, Goker E, Wachter M, Steinherz P, Tan C, Berman E, Wright JE, Rosowsky A: Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute leukemia. Blood 80:1158–1162, 1992PubMedGoogle Scholar
  44. 44.
    Goker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y, Schneiders B, Steinherz P, Tan C, Berman E, Bertino J: Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 86:677–684, 1995PubMedGoogle Scholar
  45. 45.
    Brigle KE, Spinella MJ, Sierra EE, Goldman ID: Characterization of a mutation in the reduced folate carrier in a transport defective cell line. J Biol Chem 270:22974–22979, 1995PubMedCrossRefGoogle Scholar
  46. 46.
    Matherly LH, Taub JW, Wong SC, Simpson PM, Ekizian R, Buck S, Williamson M, Amylon M, Pullen J, Camitta B, Ravindranath Y: Increased frequency of expression of elevated dihydrofolate reductase in T cell versus B-precursor acute lymphoblastic leukemia in children. Blood 90:578–589, 1997PubMedGoogle Scholar
  47. 47.
    Spencer HT, Sorrentino BP, Pui CH, Chunduru SK, Sleep SE, Blakley RL: Mutations in the gene for human dihydrofolate reductase: An unlikely cause of clinical relapse in pediatric leukemia after therapy with methotrexate. Leukemia 10:439–446, 1996PubMedGoogle Scholar
  48. 48.
    Li W, Fan J, Hochhauser D, Banerjee D, Zielinski Z, Almasan A, Yin Y, Kelly R, Wahl GM, Bertino JR: Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Proc Natl Acad Sci 92:10436–10440, 1995PubMedCrossRefGoogle Scholar
  49. 49.
    Kristensen LO, Weismann K, Hutters L: Renal function and the rate of disappearance of methotrexate from serum. Eur J Clin Pharmacol 8:439–444, 1977CrossRefGoogle Scholar
  50. 50.
    Wan SH, Huffman DH, Azarnoff DL, Stephens R, Hoogstraten B: Effect of route and administration and effusions on methotrexate pharmacokinetics. Cancer Res 34:3487–3491, 1974PubMedGoogle Scholar
  51. 51.
    Daly H, Boyle J, Roberts C, Scott G: Interaction between methotrexate and non steroidal anti inflammatory drugs. Lancet 1(8480):557, 1986PubMedCrossRefGoogle Scholar
  52. 52.
    van Meerten E, Verweij J, Schellens JH: Antineoplastic agents. Drug interactions of clinical significance. Drug Safety 12:168–182, 1995PubMedCrossRefGoogle Scholar
  53. 53.
    McLeod H: Clinically relevant drug-drug interactions in oncology. Br J Clin Pharmacol 45:539–544, 1998PubMedCrossRefGoogle Scholar
  54. 54.
    Romolo JL, Goldberg NH, Hande KR, Rosenberg SA: Effect of hydration on plasma-methotrexate levels. Cancer Treat Rep 61:1393–1396, 1977PubMedGoogle Scholar
  55. 55.
    Sonneveld P, Schultz FW, Nooter K, Hahlen K: Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following medium dose methotrexate therapy. Cancer Chemother Pharmacol 14:165–167, 1985CrossRefGoogle Scholar
  56. 56.
    Valerino DM, Johns DG, Zaharko DS, Oliverio VT: Studies of the metabolism of methotrexate by intestinal flora I. Identification and study of biological properties of the metabolite 4-amino-4-deoxy-N10 methylpteroic acid. Biochem Pharmacol 21:821–831, 1972PubMedCrossRefGoogle Scholar
  57. 57.
    Donehower RC, Hande KR, Drake JC, Chabner BA: Presence of 2,4-diamino-N10-methylpteroic acid after high dose methotrexate. Clin Pharmcol Ther 26:63–72, 1979Google Scholar
  58. 58.
    Sholar PW, Baram J, Seither R, Allegra CJ: Inhibition of folate dependent enzymes by 7-OH-methotrexate. Biochem Pharmacol 37:3531–3534, 1988PubMedCrossRefGoogle Scholar
  59. 59.
    Evans W, Relling MV, Boyett JM, Pui CH: Does pharmacokinetic variability influence the efficacy of high dose methotrexate for the treatment of children with acute lymphoblastic leukemia: What can we learn from small studies? Leukemia Res 21:435–437, 1997CrossRefGoogle Scholar
  60. 60.
    Relling MV, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH, Evans WE: Patient characteristics associated with high dose methotrexate concentrations and toxicity. J Clin Oncol 12:1667–1672, 1994PubMedGoogle Scholar
  61. 61.
    Masson E, Relling MV, Synold TW, Liu Q, Schuetz JD, Sandlund JT, Pui CH, Evans WE: Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. J Clin Invest 97:73–80, 1996PubMedCrossRefGoogle Scholar
  62. 62.
    Synold TW, Relling MV, Boyett JM, Rivera GK, Sandlund JT, Mahmoud H, Crist WM, Pui CH, Evans WE: Blast cell methotrexate polyglutamate accumulation in vivo differs by lineage, ploidy and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94:1996–2001, 1994PubMedCrossRefGoogle Scholar
  63. 63.
    Graf N, Winkler K, Betlemovic M, Fuchs N, Bode U: Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 12:1442–1451, 1994Google Scholar
  64. 64.
    Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim OP: Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single high dose methotrexate: A Scandinavian sarcoma group study. J Clin Oncol 9:1766–1775, 1991PubMedGoogle Scholar
  65. 65.
    Masson E, Zamboni WC: Pharmacokinetic optimization of cancer chemotherapy. Clin Pharmacokinetics 32:324–343, 1997CrossRefGoogle Scholar
  66. 66.
    Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP, George SL, Pui CH: Clinical pharmacokinetics of high dose methotrexate in acute lymphocytic leukemia. N Engl J Med 314:471–477, 1986PubMedCrossRefGoogle Scholar
  67. 67.
    Pui CH: Childhood leukemias. New Engl J Med 332:1618–1630, 1995PubMedCrossRefGoogle Scholar
  68. 68.
    Solheim OP, Saeter G, Finnanger AM, Stenwig AE: High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. Br J Cancer 65:956–960, 1992Google Scholar
  69. 69.
    Ong ST, Vogelzang NJ, Chemotherapy in malignant pleural mesothelioma: A review. J Clin Oncol 14:1007–1017, 1996PubMedGoogle Scholar
  70. 70.
    Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, Armand JP, Wildiers J, de Graeff A, Clavel M: Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and or recurrent squamous cell carcinoma of the head and neck: A European Organization for the Research and Treatment of Cancer Head and Neck Cooperative group study. J Clin Oncol 13:1649–1655, 1995PubMedGoogle Scholar
  71. 71.
    Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U: Combination chemotherapy as an adjuvant treatment in operable breast cancer. New Engl J Med 294:405–410, 1976PubMedCrossRefGoogle Scholar
  72. 72.
    Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C: Adjuvant cyclophosphamide, methotrexate and fluorouracil in node positive breast cancer: The results of 20 years of follow up. N Engl J Med 332:901–906, 1995PubMedCrossRefGoogle Scholar
  73. 73.
    Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1–15, 71–85, 1992Google Scholar
  74. 74.
    Early Breast Cancer Trialists Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Early Breast Cancer Trialists Collaborative Group. Lancet 352(9132):930–942, 1998CrossRefGoogle Scholar
  75. 75.
    Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, Tinazzi A, Leberati A: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16:3439–3460, 1998PubMedGoogle Scholar
  76. 76.
    Roth BJ: Chemotherapy for advanced bladder cancer. Semin Oncol 23:633–644, 1996PubMedGoogle Scholar
  77. 77.
    Stadler WM, Kuzel TM, Raghavan D, Levine E, Vogelzang NJ, Roth B, Dorr FA: Metastatic bladder cancer: Advances in treatment. Eur J Cancer 33:S23–26, 1997PubMedCrossRefGoogle Scholar
  78. 78.
    Hillcoat BL, Raghavan D, Matthews J, Kefford R, Yuen K, Woods R, Olver I, Bishop J, Pearson B, Coorey G: A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract. J Clin Oncol 7:706–709, 1989PubMedGoogle Scholar
  79. 79.
    Logothesis CJ, Dexeus FH, Finn L: A prospective randomized trials comparing MVAC and CISCA chemotherapy of patients with metastatic urothelial tumors. J Clin Oncol 8:1050–1055, 1990Google Scholar
  80. 80.
    Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghaven D, Stuart-Harris R, Sarosdy MF, Lowe BA: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 10:1066–1073, 1992PubMedGoogle Scholar
  81. 81.
    Hill ME, Cunningham D: Medical management of advanced gastric cancer. Cancer Treat Rev 24:113–118, 1998PubMedCrossRefGoogle Scholar
  82. 82.
    Bruckner HW, Lokich JJ, Stablein DM: Studies of Bakers antifol, methotrexate and razozane in advanced gastric cancer: A Gastrointestinal Tumour study group report. Cancer Treat Rep 66:1713–1717, 1982PubMedGoogle Scholar
  83. 83.
    Wils J, Klein HO, Wagener DJT, Bleiberg H, Reis H, Korsten F, Conroy T, Fickers M, Leyvraz S, Buyse M: Sequential high dose methotrexate and 5 fluorouracil combined with doxorubicin: A step ahead in the treatment of advanced gastric cancer. A trial of the EORTC Gastrointestinal (GI) tract Cooperative Group. J Clin Oncol 9:827–831, 1991Google Scholar
  84. 84.
    Rosowsky A: Development of non polyglutamable DHFR inhibitors. In: Jackman AL (ed) Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp 59–100Google Scholar
  85. 85.
    Li WW, Bertino JR: Inability of leucovorin to rescue a naturally methotrexate-resistant human soft tissue sarcoma cell line from trimetrexate cytoxicity. Cancer Res 52:6866–6870, 1992PubMedGoogle Scholar
  86. 86.
    Assaraf YG, Molina A, Schimke RT: Cross-resistance to the lipid-soluble antifolate trimetrexate in human carcinoma cells with the multdrug-resistant phenotype. J Natl Cancer Inst 81:290–294, 1989PubMedCrossRefGoogle Scholar
  87. 87.
    Assaraf YG, Borgnia MJ: Differential reversal of lipophilic antifolate resistance in mammalian cells with modulators of the multidrug resistance phenotype. Anticancer Drugs 4:395–406, 1993PubMedGoogle Scholar
  88. 88.
    Schwartz GK, Arkin H, Holland JF, Ohnuma T: Protein kinase C activity and multidrug resistance in MOLT-3 human lymphoblastic leukemia cells resistant to trimetrexate. Cancer Res 51:55–61, 1991PubMedGoogle Scholar
  89. 89.
    Li XK, Kobayashi H, Holland JF, Ohnuma T: Expression of dihydrofolate reductase and multidrug resistance genes in trimetrexate-resistant human leukemia cell lines. Leukemia Res 17:483–490, 1993CrossRefGoogle Scholar
  90. 90.
    Grem JL, Voeller DM, Geoffrey F, Horak E, Johnston PG, Allegra CJ: Determinants of trimetrexate lethality in human colon cancer cells. Br J Cancer 70:1075–1084, 1994PubMedGoogle Scholar
  91. 91.
    Stewart JA, McCormack JJ, Tong W, Low JB, Roberts JD, Blow A, Whitfield LR, Haugh LD, Grove WR, Lopez AJ: Phase I clinical and pharmacokinetic study of trimetrexate using a daily × 5 schedule. Cancer Res 48:5029–5035, 1988PubMedGoogle Scholar
  92. 92.
    Lin JT, Cashmore AR, Baker M, Dreyer RN, Ernstoff M, Marsh JC, Bertino JR, Whitfield LR, Delap R, Grillo-Lopez A: Phase I studies with trimetrexate: Clinical pharmacology, analytical methodology and pharmacokinetics. Cancer Res 47:609–616, 1987PubMedGoogle Scholar
  93. 93.
    Allegra CJ, Jenkins J, Weiss RB, Balis F, Drake JC, Brooks J, Thomas R, Curt GA: A phase I and pharmacokinetic study of trimetrexate using a 24-hour continuous-injection schedule. Invest New Drugs 8:159–166, 1990PubMedCrossRefGoogle Scholar
  94. 94.
    Bishop JF, Raghaven D, Olver IN, Reece P, Morris R, Friedlander ML: A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion. Cancer Chemother Pharmacol 24:246–250, 1989PubMedCrossRefGoogle Scholar
  95. 95.
    Fanucchi MP, Walsh TD, Fleisher M, Lokos G, Williams L, Cassidy C, Vidal P, Chou TC, Niedzwiecki D, Young CW: Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks. Cancer Res 47:3303–3308, 1987PubMedGoogle Scholar
  96. 96.
    Grochow LB, Noe DA, Dole GB, Rowinsky EK, Ettinger DS, Graham ML, McGuire WP, Donehower RC: Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: Clinical pharmacology and pharmacodynamics. J Natl Cancer Inst 81:124–130, 1989PubMedCrossRefGoogle Scholar
  97. 97.
    Huan SD, Legha SS, Raber MN, Krakoff IH: Phase I studies of trimetrexate using single and weekly dosing schedules. Invest New Drugs 9:199–206, 1991PubMedCrossRefGoogle Scholar
  98. 98.
    Jolivet J, Landry L, Pinard MF, McCormack JJ, Tong WP, Eisenhauer E: A phase I study of trimetrexate, an analog of methotrexate, administered monthly in the form of nine consecutive daily bolus injections. Cancer Chemother Pharmacol 20:167–172, 1987CrossRefGoogle Scholar
  99. 99.
    Haller DG: Trimetrexate: Experience with solid tumors. Semin Oncol 24:S18-71–S18-76, 1997Google Scholar
  100. 100.
    Eisenhauer EA, Zee BC, Pater JL, Walsh WR; Trimetrexate: Predictors of severe or life threatening toxic effects. J Natl Cancer Inst 80(16):1318–22, 1988PubMedCrossRefGoogle Scholar
  101. 101.
    Grem JL, Ellenberg SS, King SA, Shoemaker DD: Correlates of severe or life threatening toxic effects from trimetrexate. J Natl Cancer Inst 80:1313–1318, 1988PubMedCrossRefGoogle Scholar
  102. 102.
    Leiby JM: Trimetrexate: A phase 2 study in previously treated patients with metastatic breast cancer. Semin Oncol 15(2 Suppl 2):27–31, 1988PubMedGoogle Scholar
  103. 103.
    Dawson NA, Costanza ME, Korzun AH, Clamon GH, Pollak M, Vogelzang NJ, Carey RW, Norton L: Trimetrexate in untreated and previously treated patients with metastatic breast cancer: A Cancer and Leukemia Group B study. Med Pediatr Oncol.19(4):283–288, 1991PubMedCrossRefGoogle Scholar
  104. 104.
    Witte RS, Elson P, Bryan GT, Trump DL: Trimetrexate in advanced renal cell carcinoma. An ECOG phase II trial. Invest New Drugs 10(1):51–54, 1992PubMedCrossRefGoogle Scholar
  105. 105.
    Witte RS, Elson P, Khhandakar J, Trump DL: An Eastern Cooperative Oncology Group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma. Cancer 73(3):688–691, 1994PubMedCrossRefGoogle Scholar
  106. 106.
    Witte RS, Yeap BY, Trump DL: Trimetrexate in advanced hormone refractory prostate cancer. An ECOG phase II trial. Invest New Drugs 12(3):255–258, 1994Google Scholar
  107. 107.
    Vogelzang NJ, Weisman LB, Herndon JE 2nd, Antman KH, Cooper MR, Corson JM, Green MR: Trimetrexate in malignant mesothelioma: A Cancer and Leukemia Group B Phase II study. J Clin Oncol 12:1436–1442, 1994Google Scholar
  108. 108.
    Licht JD, Gonin R, Antman KH. Phase II trial of trimetrexate in patients with advanced soft tissue sarcoma: Cancer Chemother Pharmacol 28(3):223–225, 1991PubMedCrossRefGoogle Scholar
  109. 109.
    Kris MG, D'Acquisto RW, Gralla RJ, Burke MT, Marks LD, Fanucchi MP, Heelan RT: Phase II trial of trimetrexate in patients with stage III and IV non small cell lung cancer. Am J Clin Oncol 12(1):24–26,1989PubMedCrossRefGoogle Scholar
  110. 110.
    Fossella FV, Winn RJ, Holoye PY, Hallinan B, Raber M, Hoelzer K, Young JA, Readling J,Bowers B, Hong WK: Phase II trial of trimetrexate for unresectable or metastatic non small cell bronchogenic carcinoma. Invest New Drugs 10(4):331–335, 1992PubMedCrossRefGoogle Scholar
  111. 111.
    Alberts AS, Falkson G, Badata M, Terblanche AP, Schmid EU: Trimetrexate in advanced carcinoma of the esophagus. Invest New Drugs 6(4):319–321, 1988PubMedCrossRefGoogle Scholar
  112. 112.
    Falkson G, Ryan LM, Haller DG: Phase II trial for the evaluation of trimetrexate in patients with inoperable squamous cell carcinoma of the esophagus. Am J Clin Oncol 15(5):433–435, 1992PubMedCrossRefGoogle Scholar
  113. 113.
    Fleming TR, Brown TD, Ross SW, Macdonald JS: Phase II trial of Trimetrexate in advanced esophageal cancer: A south west oncology study group study. Invest New Drugs 13(4):363–365, 1996PubMedCrossRefGoogle Scholar
  114. 114.
    Ajani JA, Abbruzzese JL, Faintuch JS, Patt YZ, Boman BM, Jackson DE, Levin B, Krakoff IH: A phase II study of trimetrexate therapy for metastatic colorectal carcinoma. Cancer Invest 8(6):619–621, 1990PubMedCrossRefGoogle Scholar
  115. 115.
    Hantel A, Tangen CM, Macdonald JS, Richman SP, Pugh RP, Pollock T: Phase II trials of Trimetrexate in untreated gastric carcinoma. A Southwest Oncology Group Study. Invest New Drugs 12(2):155–157, 1994PubMedCrossRefGoogle Scholar
  116. 116.
    Ramanathan RK, Lipsitz S, Asbury RF, Qazi R, Greenberg BR, Hall DH: Phase II trial of trimetrexate for patients with advanced gastric carcinoma: An Eastern Cooperative Oncology Group study. Cancer 86(4):572–576, 1999PubMedCrossRefGoogle Scholar
  117. 117.
    Odujinrin O, Goldberg D, Doroshaw J, Leong L, Margolin K, Grove W, Varr B, Akman S: Treatment of metastatic melanoma with trimetrexate: A phase II study. Med Pediatr Oncol 18(1):49–52, 1990.PubMedCrossRefGoogle Scholar
  118. 118.
    Iscoe NA, Eisenhauer EA, Bodurtha AJ: Phase II study of trimetrexate in malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group study. Invest New Drugs 8(1):121–123, 1990PubMedCrossRefGoogle Scholar
  119. 119.
    Cairncross JG, Eisenhauer EA, Macdonald DR, Rathbone MP, Moore M, Sawka CA, MacCormick RE, Kerr I: Phase II study of Trimetrexate in recurrent anaplastic glioma. National Caner Instititute of Canada Clinical Trials Group Study. Can J Neurol Sci 17(1): 21–23, 1990Google Scholar
  120. 120.
    Smith HO, Blessing JA, Vaccarello L: Trimetrexate in the treatment of recurrent or advanced leiomyosarcomas of the uterus: A phase II study of the Gynecologic Group. Gynecol Oncol 84(1):140–144, 2002PubMedCrossRefGoogle Scholar
  121. 121.
    Fowler JM, Blessing JA, Burger RA, Maltefano JH: Phase II evaluation of oral trimetrexate in mixed mesodermal tumors of the uterus: A gynecologic oncology group study. Gynecol Oncol 85(2):311–314, 2002PubMedCrossRefGoogle Scholar
  122. 122.
    Sarris AH, Phan A, Duvic M, Romaguera J, McLaughlin P, Mesina O, King K, Medeiros LJ, Rassidakis GZ, Samuels B, Cabanillas F: Trimetrexate in relapsed T cell lymphoma with skin involvement. J Clin Oncol 20(12):2876–2880, 2002PubMedCrossRefGoogle Scholar
  123. 123.
    Brown TD, Fleming TR, Goodman PJ, Macdonald JS, Pugh RP, O'Rourke T: A randomized trial of two schedules of trimetrexate versus fluorouracil in advanced colorectal cancer: A Southwest Oncology Group study. Anticancer Drugs 6:219–223, 1995PubMedCrossRefGoogle Scholar
  124. 124.
    Gesme DH Jr, Jett JR, Schreffler DD, Su JQ, Maillard JA, Foley JF, KrookJE, Maksymiuk AW, Hatfield AK, Ebbert LP: A randomized phase II trial of amonafide or Trimetrexate in patients with advanced non-small cell lung cancer. A trial of the North Central Cancer Treatment Group. Cancer 71(9):2723–2726, 1993Google Scholar
  125. 125.
    Chang AY, Kim K, Boucher H, Bonomi P, Stewart JA, Karp DD, Blum RH: A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide inpatients with metastatic non small cell lung carcinoma: An Eastern Cooperative Oncology Group Study (E1587). Cancer 82(2):292–300, 1998PubMedCrossRefGoogle Scholar
  126. 126.
    Weiss GR, Liu PY, O'Sullivan J, Alberts DS, BrownTD, Neefe JR, Hutchins LF: A randomized phase II trial of trimetrexate or dideminin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix. Gynecol Oncol 45(3):303–306, 1992PubMedCrossRefGoogle Scholar
  127. 127.
    Szelenyi H, Hoheberger P, Lochs H, Haboubi N, Berbel WE, Thiel E, Kreuser ED: Sequential trimetrexate, 5 fluorouracil and folinic acid are effective and well tolerated in metastatic colorectal carcinoma. The phase II study group of the AIO. Oncology 58(4):273–279, 2000Google Scholar
  128. 128.
    Blanke CD, Kasimis B, Schein P, Capizzi R, Kurman M: Phase II study of Trimetrexate, fluorouracil and leucovorin for advanced colorectal cancer. J Clin Oncol 15(3): 915–920, 1997PubMedGoogle Scholar
  129. 129.
    Machiavelli MR, Salum G, Perez JE, Ortiz EH, Romero AO, Bologna F, Vallejo CT, Lacava JA, Dominguez ME, Leone BA: Double modulation of 5 fluorouracil by trimetrexate and leucovorin in patients with advanced colorectal carcinoma. Am J Clin Oncol 27(2):149–154, 2004PubMedCrossRefGoogle Scholar
  130. 130.
    Garcia AA, Leichman L, Baranda J, Pandit L, Lenz HJ, Leichman CG: Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer. Int J Gastrointest Cancer 34(2/3):79–86, 2003PubMedCrossRefGoogle Scholar
  131. 131.
    Romanini AM, Li WW, Colofiore JR, Bertino JR: Leucovorin enhances cytotoxicity of Trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells. J Natl Cancer Inst 84:1033–1038, 1992PubMedCrossRefGoogle Scholar
  132. 132.
    Conti JA, Kemeny N, Seiter K, Goker E, Tong W, Andre M, Ragusa K, Bertino JR: Trial of sequential methotrexate, fluorouracil and high dose leucovorin in previously treated patients with gastrointestinal carcinoma. J Clin Oncol 12:695–700, 1994PubMedGoogle Scholar
  133. 133.
    Blanke CD, Kasimis B, Schein P. Capizzi R, Kurman M: Phase II study of trimetrexate, fluorouracil and leucovorin for advanced colorectal cancer. J Clin Oncol 15:915–920, 1997PubMedGoogle Scholar
  134. 134.
    Punt CJ, Keizer HJ, Douma J, Skovsgaard T, Schuller J, Muller EW, Ten Napel CH, Croles JJ, Lochs H, Zhag J, Hammershaimb L: Trimetrexate as a biochemical modulator of 5 fluorouracil /leucovorin in advanced colorectal cancer: Final results of a randomized European study. Ann Oncol 13(1):81–86, 2002PubMedCrossRefGoogle Scholar
  135. 135.
    Punt CJ, Blanke CD, Zhang J, Hammershaimb L: Integrated analysis of overall survival in two randomized studies comparing 5 fluorouracil/leucovorin with or without trimetrexate in advanced colorectal cancer. Ann Oncol 13(1):92–94, 2002PubMedCrossRefGoogle Scholar
  136. 136.
    Laszlo J, Brenckman WD Jr, Morgan E, Clendeninn NJ, Williams T, Currie V, Young C: Initial clinical studies of piritrexim. NCI Monogr 5:121–125, 1987PubMedGoogle Scholar
  137. 137.
    Takimoto CH, Allegra CJ: New antifolates in clinical development. Oncology 9:649–659, 1995PubMedGoogle Scholar
  138. 138.
    Roth BJ, Manola J, Dreicer R, Graham D, Wilding G: Eastern Cooperative Oncology Group: Piritrexim in advanced refractory carcinoma of the urothelium (E3896): A phase II trial of the Eastern Cooperative Oncology Group. Invest New Drugs 20(4):425, 2002PubMedCrossRefGoogle Scholar
  139. 139.
    Khorsand M, Lange J, Feun L, Clendenin NJ, Collier M, Wilding G: Phase II trial of oral piritrexim in advanced, previously treated transitional cell cancer of the bladder. Invest New Drugs 15(2):157–163, 1997PubMedCrossRefGoogle Scholar
  140. 140.
    de Wit R, Kaye SB, Roberts JT, Stoter G, Scott J, Verweij J: Oral piritrexim, and effective treatment for metastatic urothelial cancers. Br J Cancer 67:388–390, 1993PubMedGoogle Scholar
  141. 141.
    Bleehen NM, Newman HV, Rampling RP, Ramsay JR, Roberts JT, Bedford P, Nethersell AB: A phase II study of oral piritrexim in recurrent high grade (III, IV) glioma. Br J Cancer 73(3):766–768, 1995Google Scholar
  142. 142.
    de Vries EG, Gietema JA, Workman P, Scott JE, Crawshaw A, Dobbs HJ, Dennis I, Mulder NH, Sleijfer DT, Willemse PH: A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer. Br J Cancer 68:641–644, 1993PubMedGoogle Scholar
  143. 143.
    Kris MG, Gralla RJ, Burke MT, Berkowitz LD, Marks LD, Kelson D, Heelan RT: Phase II trial of oral piritrexim (BW301U) in patients with stage III non small cell lung cancer. Cancer Treat Rep 71(7/8):763–764, 1987PubMedGoogle Scholar
  144. 144.
    Schiesel JD, Carabasi M, Magill G, Casper E, Cheng E, Marks L, Feyzi J, Clendennin NJ, Smalley RV: Oral piritrexim- a phase II study in patients with advanced soft tissue sarcoma. Invest New Drugs 10(2):97–98, 1992PubMedCrossRefGoogle Scholar
  145. 145.
    Degardin M, Domenge C, Cappelaere P, Luboinski B, Navarrete MS, Scott JE, Lefebvre JL: A phase II study of piritrexim in patients with advanced squamous cell carcinoma of the head and neck. Eur J Cancer 30A:1044–1045, 1994PubMedCrossRefGoogle Scholar
  146. 146.
    Uen WC, Huang AT, Mennel R, Jones SE, Spaulding MB, Killion K, Havlin K, Keegan P, Clendeninn NJ: A Phase II study of pyritrexim in patients with advanced squamous head and neck cancer. Cancer 69:1008–1011, 1992PubMedCrossRefGoogle Scholar
  147. 147.
    Vokes EE, Dimery IW, Jacobs CD, Karp D, Molina A, Collier MA, Eble ML, Clendeninn NJ: A phase II study of piritrexim in combination with methotrexate in recurrent and metastatic head and neck cancer. Cancer 67:2253–2257, 1991PubMedCrossRefGoogle Scholar
  148. 148.
    Feun LG, Gonzalez R, Savaraj N, Hanlon J, Collier M, Robinson WA, Clendeninn NJ: Phase II trials of piritrexim in metastatic melanoma using intermittent, low dose administration. J Clin Oncol 9:464–467, 1991PubMedGoogle Scholar
  149. 149.
    Feun LG, Robinson WA, Savaraj N, Gonzalez R, Liebmann A, Offenhauser K, Clendeninn NJ: Phase II trial of piritrexim and DTIC using an alternating dosing schedule in metastatic melanoma. Am J Clin Oncol 18:488–490, 1995PubMedCrossRefGoogle Scholar
  150. 150.
    Feun LG, Savaraj N, Benedetto P, Waldman S, Collier M, Clendennin NJ: Oral piritrexim in advanced bladder cancer: An effective drug after progression on MVAC chemotherapy? Am J Clin Oncol 17(5):448–451, 1994PubMedGoogle Scholar
  151. 151.
    Laszlo J, I and HJ, Sedwick WD: Overcoming methotrexate resistance by a lipophilic antifolate (BW 301U): From theory to models to practice. Adv Enzyme Regul 24:357–375, 1985Google Scholar
  152. 152.
    Cvitkovic E, Domenge C, Gandia D: Case report of acquired piritrexim resistance and collateral methotrexate sensitivity in recurrent squamous cell carcinoma of the head and neck. J Natl Cancer Inst 4;85(15):1248, 1993CrossRefGoogle Scholar
  153. 153.
    Grant SC, Kris MG, Young CV, Sirotnak FM: Edatrexate: An antifolate with antitumor activity: A review. Cancer Invest 11:36–45, 1993PubMedCrossRefGoogle Scholar
  154. 154.
    Schmid FA, Sirotnak FM, Otter GM, DeGraw JI: New antifolates of 10-deazaaminopterin series: Markedly increased antitumor activity of the 10-ethyl analogue compared to the parent compound and methotrexate against some human tumor xenografts in nude mice. Cancer Treat Rep 69:551–553, 1985PubMedGoogle Scholar
  155. 155.
    Meyers FJ, Lew D, Lara PN Jr, Williamson S, Marshall E, Balcerzak SP, Rivkin SE, Samlowski W, Crawford ED: Phase II trial of edatrexate in relapsed or refractory germ cell tumors: A South West Oncology Group study (SWOG9124). Invest New Drugs 16(4):347–351, 1998–1999CrossRefGoogle Scholar
  156. 156.
    Dreicer R, Propert KJ, Kuzel T, Kirkwood JM, O'Dwyer PJ, Loehrer PJ: A phase II trial of edatrexate in patients with advanced renal cell carcinoma. An Eastern Cooperative Group Trial. Am J Clin Oncol 20(3):251–253, 1997PubMedCrossRefGoogle Scholar
  157. 157.
    Broun ER, Iseminger KA, Rose PG, Lentz SL, Malfetano JH, Lincoln S, Mannel R: A phase II trial of edatrexate in previously treated squamous cell cervical cancer: A Gynecologic Oncology Group study. Am J Clin Oncol 20(1):78–80, 1997PubMedCrossRefGoogle Scholar
  158. 158.
    Clamon GH, Riggs CE Jr, Dreicer R, Hohl RJ: Phase II study of edatrexate in patients with metastatic colorectal cancer. Invest New Drugs 13(4):359–361, 1996PubMedCrossRefGoogle Scholar
  159. 159.
    Kemeny N, Israel K, O'Hehir M: Phase II trial of Edam in patients with advanced colorectal cancer. Am J Clin Oncol 13(1):42–44, 1990PubMedCrossRefGoogle Scholar
  160. 160.
    Broun ER, Iseminger KA, Bookman M: A phase II trial of edatrexate in previously treated ovarian cancer. A Gynecologic Oncology Group Study. Am J Clin Oncol 8(2):164–166, 1995Google Scholar
  161. 161.
    Pazdur R, Moore DF, Bready B, Giannone L, Maldonado A, Lin YG, Fueger RH, Winn RJ, Levin B: Phase II trials of edatrexate in patients with advanced hepatocellular carcinoma Ann Oncol 5(7):646–648, 1994PubMedGoogle Scholar
  162. 162.
    Moore DF Jr, Pazdur R, Abbruzzese JL, Ajani JA, Dubovsky DW, Wade JL 3rd, Belt RJ, Mangold C, Bready B, Winn RJ: Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma. Ann Oncol 5(3):286–287, 1994PubMedGoogle Scholar
  163. 163.
    Weisenfeld M, Jett JR, Su JQ, Braich TA, Kardinal CG, Mailliard JA, Veeder MH, Morton RF, Michalak JC: Phase II trial of edatrexate in small cell lung cancer. Cancer 73(4):1189–1193, 1994CrossRefGoogle Scholar
  164. 164.
    Schultz PK, Kelly WK, Begg C, Liebertz C, Cohen L, Scher HI: Post therapy change in prostate specific antigen levels as a clinical trial endpoint in hormone refractory prostatic cancer: A trial with 10-ethyl-deaza-aminopterin. Urology 44(2):237–242, 1994PubMedCrossRefGoogle Scholar
  165. 165.
    Kuebler JP, Benedetti J, Schuller DE, Ensley J, Grunberg SM, Muirhead MJ, Richert-Boe KE, Marshall ME: Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study. Invest New Drugs 12(4):341–344, 1994Google Scholar
  166. 166.
    Green MD, Sherman P, Zalcberg J: Phase II study of 10-EdAM in patients with squamous cell carcinoma of the head and neck, previously untreated with chemotherapy. Invest New Drugs 10(1):31–34, 1992PubMedCrossRefGoogle Scholar
  167. 167.
    Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, Armand JP, Wildiers J, Clavel M, Kirkpatrick A: A phase II trial of 10-ethyl-10-deaza-aminopterin, a novel antifolate, in patients with advanced and /or recurrent squamous cell carcinoma of the head and neck. The EORTC Head and Neck Cancer Cooperative Group. Ann Oncol 3(3):223–226, 1992Google Scholar
  168. 168.
    Vandenberg TA, Pritchard KI, Eisenhauer EA, Trudeau ME, Norris BD, Lopez P, Verma SS, Buckamn RA, Muldal A: Phase II study of weekly edatrexate as first line chemotherapy for metastatic breast cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 11(7):1241–1244, 1993PubMedGoogle Scholar
  169. 169.
    Schornagel JH, van der Vegt S, Verweij J, de Graeff A, Dullemond-Westland A, van Deijk WA, ten Bokkel Huinink WW: Phase II study of edatrexate in chemotherapy naïve patients with metastatic breast cancer. Ann Oncol 3(7):549–552, 1992PubMedGoogle Scholar
  170. 170.
    Verma S, Quirt IC, Eisenhauer EA, Iscoe NA, Young VJ, Bodurtha AJ, Davidson J: A phase II study of weekly edatrexate (10 EDAM) in metastatic melanoma. A National Cancer Institute of Canada Clinical Trials Group study. Ann Oncol 4(3):254–255, 1993Google Scholar
  171. 171.
    Casper ES, Schwartz GK, Johnson B, Kelsen DP: Phase II trial of edatrexate with advanced pancreatic adenocarcinoma. Invest New Drugs 10(4):313–316, 1992PubMedCrossRefGoogle Scholar
  172. 172.
    Casper ES, Christman KL, Schwartz GK, Johnson B, Brennan MF, Bertino JR: Edatrexate in patients with soft tissue sarcoma. Activity in malignant fibrous histiocytoma. Cancer 72(3):766–770, 1993Google Scholar
  173. 173.
    Knowling M, Bramwell V, Eisenhauer E, Boos G, Bodurtha A, Quirt I: Phase II trial of 10-EDAM in advanced soft tissue sarcoma. A study of the Canadian Sarcoma group and National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 5(8):766–768, 1994Google Scholar
  174. 174.
    Souhami RL, Rudd RM, Spiro SG, Allen R, Lamond P, Harper PG: Phase II study of edatrexate in stage III and IV non small cell lung cancer. Cancer Chemother Pharmacol 30(6):465–468, 1992PubMedCrossRefGoogle Scholar
  175. 175.
    Lee JS, Libshitz HI, Murphy WK, Jeffries D, Hong WK: Phase II study of 10-ethyl-10-deaza-aminopterin (10-Edam;CGP 30 694) for stage IIIb or IV non-small cell lung cancer. Invest New Drugs 8(3):299–304, 1990PubMedCrossRefGoogle Scholar
  176. 176.
    Shum KY, Kris MG, Gralla RJ, Burke MT, Marks LD, Heelan RT: Phase II study of 10-ethyl-10-deaza-aminopterin in patients with stage III and IV non small cell lung cancer. J Clin Oncol 6(3):466–450, 1988Google Scholar
  177. 177.
    Kindler HL, Belani CP, Herndon JE 2nd, Vogelzang NJ, Suzuki Y, Green MR: Edatrexate (10-ethyl-deaza-aminopterin) (NSC #626715) with or without leucovorin rescue for malignant mesothelioma. Sequential phase II trials by the cancer and leukemia group B. Cancer 86(10):1985–1991, 1999Google Scholar
  178. 178.
    Gandara DR, Edelman MJ, Crowley JJ, Lau DH, Livingston RB: Phase II trial of edatrexate plus carboplatin in metastatic non small cell lung cancer: A Southwest Oncology Group Study. Cancer Chemother Pharmacol 41(1):75–78, 1997PubMedCrossRefGoogle Scholar
  179. 179.
    Lee JS, Libshitz HI, Fossella FV, Murphy WK, Pang AC, Lippman SM, Shin DM, Dimery IW, Glisson BS, Hong WK: Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non small cell lung cancer. Cancer 68(5):959–964, 1991PubMedCrossRefGoogle Scholar
  180. 180.
    Colon-Otero G, Niedringhaus RD, Hillman SH, Geyer S, Sloan J, Krook JE, Windschitl HE, Marks RS, Wiesenfeld M, Tschetter LK, Jett JJ: North Central Cancer Treatment Group. A Phase II trial of edatrexate, vinblastine, Adriamycin, cisplatin, and filgrastim (EVAG/G-CSF) in patients with non small cell carcinoma of the lungs: A North Central Cancer Treatment Group Trial. Am J Clin Oncol 24(6):51–55, 2001CrossRefGoogle Scholar
  181. 181.
    Huber MH, Dimery IW, Benner SE, Lippman SM, Shirinian M, Esparaz B, Frenning D, Gillory-Perez C, Hong WK: Phase II study of carboplatin and edatrexate (10-EdAM) with leucovorin rescue for patients with recurrent squamous cell carcinoma of the head and neck. Invest New Drugs 12(4):327–331, 1994PubMedCrossRefGoogle Scholar
  182. 182.
    Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, Armand JP, Wildiers J, de Graeff A, Clavel M: Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cooperative Group study. J Clin Oncol 13(7):1649–1655, 1995PubMedGoogle Scholar
  183. 183.
    Gralla RJ, Lee JS, Kris MG, Comis RL, Sridhar KS, Crawford J, Hirsh V, Wernz JC, Belani CP, Vokes E: Multicenter, randomized trial comparing the combination of edatrexate, mitomycin and vinblastine (EMV) with mitomycin and vinblastine (MV) in 673 patients with stage III and IV non-small cell lung cancer. Abstract. Proc Am Soc Clin Oncol 13:1161, 1994Google Scholar
  184. 184.
    Degraw JI, Colwell WT, Piper JR, Sirotnak FM: Synthesis and antitumor activity of 10 propargyl-10-deazaminnopterin. J Med Chem 36(15):2228–2231, 1993PubMedCrossRefGoogle Scholar
  185. 185.
    Krug LM, Ng KK, Kris MG, Miller VA, Tong W, Heelan RT, Leon L, Leung D, Kelly J, Grant SC, Sirotnak FM: Phase I and pharmacokinetic study of 10-propargy-10 deazaaminopterin, a new antifolate. Clin Cancer Res 6(9):3493–3498, 2000PubMedGoogle Scholar
  186. 186.
    Krug LM, Azzoloi CG, Kris MG, Miller VA, Khokhar NZ, Tong W, Ginsberg MS, Venkatraman E, Tyson L, Pizzo B, Baez V, Ng KK, Sirotnak FM: 10 propargyl-10-deazaaminopterin: An antifolate with activity in patients with previously treated non small cell lung cancer. Clin Cancer Res 9(6):2072–2078, 2003PubMedGoogle Scholar
  187. 187.
    Houghton P: Thymineless Death. In: Jackman AL (ed) Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 423–426Google Scholar
  188. 188.
    Jones TR, Calvert AH, Jackman AL, Eakin MA, Smithers MJ, Betteridge RF, Newell DR, Hayter AJ, Stocker A, Harland SJ, Davies LC, Harrap KR: Quinazoline antifolates inhibiting thymidylate synthase: Variation of the N10 substituent. J Med Chem 28:1468–1476, 1985PubMedCrossRefGoogle Scholar
  189. 189.
    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, 1981PubMedGoogle Scholar
  190. 190.
    Jackson RC, Jackman AL, Calvert AH: Biochemical effects of the quinazoline inhibitor of thymidylate synthetase, CB 3717 on human lymphoblastoid cells. Biochem Pharmacol 32:3783–3790, 1983PubMedCrossRefGoogle Scholar
  191. 191.
    Cantwell BM, Earnshaw M, Harris AL: Phase II study of a novel antifolate, N10-propargyl-5, 8 dideazafolic acid (CB3717) in malignant mesothelioma. Cancer Treat Rep 70:1335–1336, 1986PubMedGoogle Scholar
  192. 192.
    Cantwell BM, Macaulay V, Harris AL, Kaye SB, Smith IE, Milsted RA, Calvert AH: Phase II study of the antifolate N10 propargy-5, 8-dideazafolic acid (CB3717) in advanced breast cancer. Eur J Cancer Clin Oncol 24:733–736, 1988PubMedCrossRefGoogle Scholar
  193. 193.
    Harding MJ, Cantwell BM, Milstead RA, Harris AL, Kaye SB: Phase II study of a novel antifolate, N10-propargyl, 5, 8, dideazafolic acid (CB3717) in colorectal cancer. Br J Cancer 57:628–629, 1988PubMedGoogle Scholar
  194. 194.
    Calvert AH, Newell DR, Jackman AL, Gumbrell LA, Sikora E, Grzelakowska-Sztabert B, Bishop JA, Judson IR, Harland SJ, Harrap KR: Recent preclinical and clinical studies with the thymidylate synthase inhibitor N10-propargyl-5, 8 dideazafolic acid (CB3717). NCI Monograph 5:231–218, 1987Google Scholar
  195. 195.
    Jackman AL, Farrugia DC, Gibson W, Kimbell R, Harrap KR, Stephens TC, Azab M, Boyle FT: ZD 1694 (Tomudex): A new thymidylate synthase inhibitor with activity in colorectal cancer. Eur J Cancer 31A:1277–1282, 1995PubMedCrossRefGoogle Scholar
  196. 196.
    Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM, Jansen G: Carrier-and receptor-mediated transport of folate antagonists targeting folate dependent enzymes: Correlates of molecular structure and biological activity. Molec Pharmacol 48:459–471, 1995Google Scholar
  197. 197.
    Hughes LR, Stephens TC, Boyle FT: Raltitrexed (TomudexTM), a highly polyglutamable antifolate thymidylate synthase inhibitor. In: Jackman AL (ed) Anti Cancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 147–165Google Scholar
  198. 198.
    Jackman AL, Taylor GA, Calvert AH, Karrap KR: Modulation of the antimetabolic effects: Effects of thymidine on the efficacy of the quinazoline based thymidylate synthetase inhibitor, CB 3717. Biochem Pharmacol 33:3269–3275, 1984PubMedCrossRefGoogle Scholar
  199. 199.
    Clarke SJ, Hanwell J, de Boer M, Planting A, Verweij J, Walker M, Smith R, Jackman AL, Hughes LR, Kennealey GT, Judson IR: Phase I trial of ZD1694 (Tomudex), a new folate based, thymidylate synthase inhibitor. J Clin Oncol 14: 1495–1503, 1996PubMedGoogle Scholar
  200. 200.
    Beale P, Clarke S: Tomudex. In: Jackman AL (ed) Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 167–181Google Scholar
  201. 201.
    Jackman AL, Boyle FT, Harrap KR: TomudexTM (ZD 1694): From concept to care, a programme in rational drug discovery. Invest New Drugs 14:305–316, 1996PubMedCrossRefGoogle Scholar
  202. 202.
    Zalcberg JR, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I: ZD1694: A novel thymidylate inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. J Clin Oncol 14:716–721, 1996PubMedGoogle Scholar
  203. 203.
    Sato A, Kurihara M, Horikoshi N, Aiba K, Kikkawa N, Shirouzu K, Mitachi Y, Sakata Y, Wakui A: Phase II study of raltitrexed (Tomudex) in chemotherapy-pretreated patients with advanced colorectal cancer. Tomudex Cooperative Study Group. Anticancer Drugs 10(8):741–748, 1999Google Scholar
  204. 204.
    Tsavaris N, Kosmas C, Vadiaka M, Kontos A, Fotia M, Angelopoulou A, Vrizidis N, Soulla M, Sougioultzis S, Koufos Ch: Raltitrexed (Tomudex) administration in patients failing multiple prior chemotherapy regimens in advanced colorectal cancer: A pilot study. Invest New Drugs 20(1):133–136, 2002PubMedCrossRefGoogle Scholar
  205. 205.
    Tsavaris N, Kosmas C, Vadiaka M, Koufos C: Raltitrexed (Tomudex) administration in patients with relapsed metastatic colorectal cancer after weekly irinotecan/5-Fluorouracil/Leucovorin chemotherapy. BMC Cancer 2(1):2, 2002CrossRefGoogle Scholar
  206. 206.
    Smith I, Jones A, Spielmann M, Namer M, Green MD, Bonneterre J, Wander HE, Hatschek T, Wilking N, Zalcberg J, Spiers J, Seymour L: A phase II study in advanced breast cancer: ZD1694 (‘pTomudex’) a novel direct and specific thymidylate synthase inhibitor. Br J Cancer 74(3):479–481, 1996PubMedGoogle Scholar
  207. 207.
    Meropol NJ, Pazdur R, Vincent M, Willson JK, Kelsen DP, Douglass HO Jr: A phase II study of ZD1694 in patients with advanced gastric cancer. Am J Clin Oncol 19(6):628–630, 1996PubMedCrossRefGoogle Scholar
  208. 208.
    Pazdur R, Meropol NJ, Casper ES, Fuchs C, Douglass HO Jr, Vincent M, Abbruzzese JL: Phase II trial of ZD1694 (Tomudex) in patients with advanced pancreatic cancer. Invest New Drugs 13(4):355–358, 1996PubMedCrossRefGoogle Scholar
  209. 209.
    Blay JY, Judson I, Rodenhuis S, Hermans C, Smith M, van Glabbeke M, Verweij J: Phase II study of raltitrexed (‘Tomudex’) for patients with advanced soft tissue sarcomas refractory to doxorubicin containing regimens. Anticancer Drugs 10(10):873–877, 1999PubMedCrossRefGoogle Scholar
  210. 210.
    Woll PJ, Basser R, Le Chevalier T, Drings P, Perez Manga G, Adenis A, Seymour L, Smith F, Thatcher N: Phase II trial of raltitrexed (‘Tomudex’) in advanced small cell lung cancer. Br J Cancer 76(2):264–265, 1997PubMedGoogle Scholar
  211. 211.
    Baas P, Ardizzoni A, Grossi F, Nackaerts K, Numico G, Van Marck E, van de Vijver M, Monetti F, Smid-Geirnaerdt MJ, van Zandwijk N, Debruyne C, Legrand C, Giaccone G: EORTC Lung Cancer Group: The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: An EORTC phase II study (08992). Eur J Cancer 39(3):353–357, 2003PubMedCrossRefGoogle Scholar
  212. 212.
    Muggia FM, Blessing JA, Homesley HD, Sorosky J: Tomudex (ZD1694, NSC 639186) in platinum pretreated recurrent epithelial ovarian cancer: A phase II study by the Gynecologic Oncology Group. Cancer Chemother Pharmacol 42(1):68–70, 1998PubMedCrossRefGoogle Scholar
  213. 213.
    Samlowski WE, Lew D, Kuebler PJ, Kolodziej MA, Medina JE, Mangan KF, Moore DF Jr, Schuller DE, Ensley JF: Evaluation of Tomudex in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A Southwest Oncology Group study. Invest New Drugs 16(3):271–274, 1998–1999CrossRefGoogle Scholar
  214. 214.
    Clarke SJ, Zalcberg J, Olver I, Mitchell PL, Rischin D, Dalley D, Green M, Davidson YE: Open label, multicenter phase II study of raltitrexed (Tomudex) in patients with inoperable squamous cell carcinoma of the head and neck. Ann Oncol 11(2): 239–241, 2000PubMedCrossRefGoogle Scholar
  215. 215.
    Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G: Final results of a randomized trial comparing Tomudex (raltitrexed) with 5 flourouracil plus leucovorin in advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. Ann Oncol 7:961–965, 1996Google Scholar
  216. 216.
    Pazdur R, Vincent M: Raltitrexed (Tomudex) versus 5 fluorouracil and leucovorin (5FU +LV) in patients with advanced colorectal cancer (ACC): Results of a randomized, multicenter, North American Trial. Abstract. Proc Am Soc Clin Oncol 16:801, 1997Google Scholar
  217. 217.
    Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, Kerr D, Possinger K, Hietschold SM: Open randomized multicenter trial of raltitrexed versus fluorouracil plus high dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943–2952, 1998Google Scholar
  218. 218.
    Maughan T, James R, Kerr D, Ledermann J, McArdle C, Seymour M, Johnston C, Stephens R: Excess treatment related deaths and impaired quality of life show raltitrexed is inferior to infusional 5FU regime in the palliative chemotherapy of advanced colorectal cancer (CRC): Final results of MRC CR06. Abstract. Ann Oncol 11 (Suppl. 4), 43:185O, 2000Google Scholar
  219. 219.
    Douillard J, Michel P, Gamelin E, Conroy T, Francois E, Raoul J, Becouarn Y, Bertheault F Cvitkovic S, Nasca S, Ychou M, Fandi A, Seitz J: Raltitrexed (Tomudex) plus oxaliplatin: An active combination for first line chemotherapy in patients with metastatic colorectal cancer. Abstract. Proc Am Soc Clin Oncol 19:971, 2000Google Scholar
  220. 220.
    Santini D, Massacesci C, D'Angelillo RM, Marcuccci F, Campisis C, Vincenzi B, Pilone A, Bianco V, Bonsignori M, Tonini G: Raltitrexed plus weekly oxaliplatin as first line chemotherapy in metastatic colorectal cancer: A multicenter non-randomized phase II study. Med Oncol 21(1):59–66, 2004PubMedCrossRefGoogle Scholar
  221. 221.
    Neri B, Doni L, Fulignati C, Perfetto F, Turrini M, Andreoli F, Pantalone D, Pernice LM, Taruffi F, Martini V, Poma A, Valeri A, Bacci G, Sancez L, Moretti R: Raltitrexed plus oxaliplatin as first line chemotherapy in metastatic colorectal carcinoma: A multicentric phase II trial. Anticancer Drugs 13(7):719–724, 2002PubMedCrossRefGoogle Scholar
  222. 222.
    Seitz JF, Bennouna J, Paillot B, GamelinE, Francois E, Conroy T, Raoul JL, Becouarn Y, Bertheault-Cvitkovic F, Ychou M, Nasca S, Fandi A, Barthelemy P, Douillard JY: Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non pretreated metastatic colorectal cancer patients. Ann Oncol 13(7):1072–1079, 2002PubMedCrossRefGoogle Scholar
  223. 223.
    Cascinu S, Graziano F, Ferrau F, Catalano V, Massacesi C, Santini D, Silva RR, Barni S, Zaniboni A, Battelli N, Siena S, Giordani P, Mari D, Baldelli AM, Antognoli S, Maisano R, Priolo D, Pessi MA, Tonini G, Rota S, Labianca R: Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the study of Gastrointestinal Tract Carcinomas (GISCAD). Ann Oncol 13(5):716–720, 2002PubMedGoogle Scholar
  224. 224.
    Scheithauer W, Kornek GV, Schuell B, Ulrich Pur H, Penz M, Raderer M, Sale T, Haider K, Kwasny W, Depisch D: Oxaliplatin plus raltitrexed in patients with advanced colorectal carcinoma: Results of a phase I-II trial. Cancer 91(7):1264–1271, 2001PubMedCrossRefGoogle Scholar
  225. 225.
    Cortinovis D, Bajetta E, Di Bartolomeo M, Dognini G, Beretta E, Ferrario E, Ricotta R, Buzzoni R: Raltitrexed plus oxaliplatin in the treatment of metastatic colorectal cancer. Tumori 90(2):186–191, 2004PubMedGoogle Scholar
  226. 226.
    Martoni A, Mini E, Pinot C, Gentile Al, Nobili S, Dentico P, Marino A, Scicolone S, Angelelli B, Mazzei T: Oxaliplatin plus raltitrexed in the treatment of patients with advanced colorectal cancer: A phase II study. Anticancer Res 23(1B):687–691, 2003PubMedGoogle Scholar
  227. 227.
    Laudani A, Gebbia V, Leonardi V, Savio G, Borsellino N, Cusimano MP, Calabria C, Stefano R, Agostara B: Activity and toxicity of oxaliplatin plus raltitrexed in 5-fluorouracil refractory metastatic colorectal adenocarcinoma. Anticancer Res 24 (2C):1139–1142, 2004PubMedGoogle Scholar
  228. 228.
    Comella P, Casaretti R, Crucitta E, DeVita F, Palmeri S, Avallone A, Oditura M, De Luca L, Del Prete S, Catalano G, Lorusso V, Comella G: Oxaliplatin plus raltitrexed and leucovorin modulated 5 fluorouracil iv bolus: A salvage regimen for colorectal cancer patients. Br J Cancer 86(12):1871–1875, 2002PubMedCrossRefGoogle Scholar
  229. 229.
    Scheithauer W, Kornek GV, Schuell B, Ulrich Pur H, Penz M, Raderer M, Lang F, Schneeweiss B, Lenauer A, Depisch D: Secondline treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy. Ann Oncol 12(5):709–714, 2001PubMedCrossRefGoogle Scholar
  230. 230.
    Feliu J, Salud A, Escudero P, Lopez-Gomez L, Pericay C, Castanon C, de Tejada MR, Rodriguez-Garcia JM, Martinez MP, Martin MS, Sanchez JJ, Baron MG; Oncopaz Cooperative Group and Associated Hospitals: Irinotecan plus raltitrexed as first line treatment in advanced colorectal cancer: A phase II study. Br J Cancer 90(8):1502–1507, 2004PubMedCrossRefGoogle Scholar
  231. 231.
    Carnaghi C, Rimassa L, Garassino I, Zucali PA, Masci G, Fallini M, Morenghi E, Santoro A: Irinotecan and raltitrexed: An active combination in advanced colorectal cancer. Ann Oncol 13(9):1424–1429, 2002PubMedCrossRefGoogle Scholar
  232. 232.
    Aparicio J, Vincent JM, Maetsu I, Garcera S, Busquier I, Bosch C, Llorca C, Diaz R, Fernandez-Martos C, Galan A: Multicenter phase II trial evaluating a three weekly schedule of irinotecan plus raltitrexed in patients with 5 fluorouracil refractory advanced colorectal cancer. Ann Oncol 14(7):1121–1125, 2003PubMedCrossRefGoogle Scholar
  233. 233.
    Cascinu S, Silva RR, Labianca R, Barni S, Mattioli R, Martignoni G, Frontini L, GaspariniG, Catalano V, Baldelli AM, Giuliodori L, Agostinelli R, Catalano G: A phase II study of Tomudex alternated with methotrexate, fluorouracil, leucovorin as first line chemotherapy of metastatic colorectal cancer. Ann Oncol 10(8):985–987, 1999PubMedCrossRefGoogle Scholar
  234. 234.
    Rosati G, Rossi A, Germano D, Regguardo G, Manzione L: Raltitrexed ad mitomycin C as third line chemotherapy for colorectal cancer after combination regimens including 5 fluorouracil, irinotecan and oxaliplatin: A phase II study. Anticancer Res 23(3C):2981–2985, 2003PubMedGoogle Scholar
  235. 235.
    Comella P, De Vita F, Mancarella S, DeLucia L, Biglietto M, Casaretti R, Farris A, Ianiello GP, Lorusso V, Avallone A, Carteni G, Leo SS, Catalano G, De Lena M, Comella G: Biweekly irinotecan or raltitrexed plus 6S leucovorin and bolus 5 fluorouracil in advanced colorectal carcinoma: A Southern Italy Cooperative Oncology Group phase II-III randomized trial. Ann Oncol 11(10):1323–1333, 2000PubMedCrossRefGoogle Scholar
  236. 236.
    Van Laethem JL, Van Maele Ph, Polus M, Demols A, Houbiers Gh, Leleux A, Schurmans P, D'Haens G, Recloux P, Caenepeel P, Ryssaert T, Daems K, Verslype C, Van Cutsem E, Peeters M: Raltitrexed (Tomudex) and gemcitabine (Gemzar) in advanced pancreatic carcinoma: A Belgian multicenter phase II study. Abstract. Proc Am Soc Clin Oncol 21:547, 2002Google Scholar
  237. 237.
    Kralidis E, Aebi S, Friess H, Buchler MW, Borner MM: Activity of raltitrexed and gemcitabine in pancreatic cancer. Ann Oncol 14(4):574–579, 2003PubMedCrossRefGoogle Scholar
  238. 238.
    Mackay HJ, McInnes A, Paul J, Raby N, Lofts FJ, McDonald AC, Soukop M, Fullarton GM, Harris AL, Garcia-Vargas J, Evans TR: A phase II study of epirubicin, cisplatin and raltitrexed combination chemotherapy (ECT) in patients with advanced oesophageal and gastric adenocarcinoma. Abstract. Ann Oncol 12(10):1407, 2001PubMedCrossRefGoogle Scholar
  239. 239.
    Schmid KE, Kornek GV, Schull B, Raderer M, Lenauer A, Depisch D, Lang F, Scheithauer W: Second line treatment of advanced gastric cancer with oxaliplatin plus raltitrexed. Onkologie 26(3):255–258, 2003PubMedCrossRefGoogle Scholar
  240. 240.
    Ulrich-Pur H, Raderer M, Verena Kornek G, Schull B, Schmid K, Haider K, Kwasny W, Depisch D, Schneeweiss B, Lang F, Scheithauer W: Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine pretreated advanced pancreatic adenocarcinoma. Br J Cancer 88(8):1180–1184, 2003PubMedCrossRefGoogle Scholar
  241. 241.
    Caponigro F, Rosati G, De Rosa P, Avallone A, De Rosa V, De Lucia L, Comella P, Comella G: Cisplatin, raltitrexed, levofolinic acid and 5 fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: A phase II randomized study. Oncology 63(3):232–238, 2002PubMedCrossRefGoogle Scholar
  242. 242.
    Decreux M, Fizazi K, Daniel C, Ruffie P, Kabouche A, Fandi A, Smith M, Armand JP: Updated results of a phase I trial of tomudex (T) in combination with oxaliplatin (L-OHP) in advanced solid tumors: A promising and active combination. Abstract. Ann Oncol 9 (suppl 4):6020, 1998Google Scholar
  243. 243.
    Maisano R, Caristi N, Toscano G, Aragona M, Spadaro P, Amadio P, Mare M, Zavettieri M, La Torre F: Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study. Tumori 87(6):391–393, 2001PubMedGoogle Scholar
  244. 244.
    Fizazi K, Doubre H, Le Chevalier T, Riviere A, Viala J, Daniel C, Robert L, Barthelemy P, Fandi A, Ruffie P: Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: Results of a phase II study. J Clin Oncol 21(2):349, 2003PubMedCrossRefGoogle Scholar
  245. 245.
    van Meerbeeck JP, Manegold C, Gaafar R, Van Klaveren R J,Vincent M, Legrand C, Debruyne C, Giaccone G: A randomized phase III study of cisplatin with or without raltitrexed in patients (pts) with malignant pleural mesothelioma (MPM): An intergroup study of the EORTC Lung Cancer Group and NCIC. Abstract. Proc Am Soc Clin Oncol 23:7021, 2004Google Scholar
  246. 246.
    Van Cutsem E, Cunningham D, Maroun J, Cervantes A, Glimelius B: Raltitrexed: current clinical status and future directions. Annals Oncol 13:513–522, 2002CrossRefGoogle Scholar
  247. 247.
    Zalcberg J: Overview of the tolerability of ‘Tomudex’(raltitrexed): Collective clinical experience in advanced colorectal cancer. Anticancer Drugs 8 (Suppl 2):S17–S22, 1997PubMedCrossRefGoogle Scholar
  248. 248.
    Anonymous. Drug company decision to end cancer trial (Editorial). Lancet 354:1054, 1999Google Scholar
  249. 249.
    Beale P, Judson I, Hanwell J, Berry C, Aherne W, Hickish T, Martin P, Walker M: Metabolism, excretion and pharmacokinetics of a single dose of [14C]-raltitrexed in cancer patients. Cancer Chemother Pharmacol 42(1):71–76, 1998PubMedCrossRefGoogle Scholar
  250. 250.
    Judson I, Maughan T, Beale P, Primrose J, Hoskin P, Hanwell J, Berry C, Walker M, Sutcliffe F: Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694). Br J Cancer 78(9):1188–1193, 1998PubMedGoogle Scholar
  251. 251.
    Farrugia DC, Aherne GW, Brunton L, Clarke SJ, Jackman AL: Leucovorin rescue from raltitrexed (Tomudex) induced antiproliferative effects: in vitro cell line and in vivo mouse studies. Clin Cancer Res 6:3646–3656, 2000PubMedGoogle Scholar
  252. 252.
    Stevenson JP, Redlinger M, Kluijtmans LA, Sun W, Algazy K, Giantonio B, Haller DG, Hardy C, Whitehead AS, O'Dwyer PJ: Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer. J Clin Oncol 19(20):4081–4087, 2001PubMedGoogle Scholar
  253. 253.
    Takemura Y, Gibson W, Kimbell R, Kobayashi H, Miyachi H, Jackman AL: Cellular pharmacokinetics of ZD1694 in cultured human leukemia cells sensitive, or made resistant to this drug. J Cancer Res Clin Oncol 122:109–117, 1996PubMedCrossRefGoogle Scholar
  254. 254.
    Jackman AL, Kelland LR, Kimbell R, Brown M, Gibson W, Aherne GW, Hardcastle A, Boyle FT: Mechanisms of acquired resistance to the quinazoline synthase inhibitor, ZD 1694 (Tomudex) in one mouse and three human cell lines. Br J Cancer 71:914–924, 1995PubMedGoogle Scholar
  255. 255.
    Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, Leichman L: Thymidylate synthase gene and protein expression correlate and are associated with response to 5 fluorouracil in human colorectal and gastric tumors. Cancer Res 55:1407–1412, 1995PubMedGoogle Scholar
  256. 256.
    Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Garcia Y, Li J, Leichman L: Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. J Clin Oncol 14:176–182, 1995Google Scholar
  257. 257.
    Pestalozzi BC, Peterson HF, Gelber RD, Goldhirsch A, Gusterson BA, Trihia H, Lindtner J, Cortes-Funes H, Simmoncini E, Byrne MJ, Golouh R, Rudenstam CM, Castiglione-Gertsch M, Allegra CJ, Johnston PG: Prognostic importance of thymidylate synthase expression in early breast cancer. J Clin Oncol 15:1923–1931, 1997PubMedGoogle Scholar
  258. 258.
    Farrugia DC, Ford HE, Cunningham D, Danenberg KD, Danenberg PV, Brabender J, McVicar AD, Aherne GW, Hardcastle A, McCarthy K, Jackman AL: Thymidylate synthase expression n advanced colorectal cancer predicts for response to raltitrexed. Clin Cancer Res 9(2):792–801, 2003PubMedGoogle Scholar
  259. 259.
    Goh BC, Ratain MJ, Bertucci D, Smith R, Mani S, Vogelzang NJ, Schilsky RL, Hutchison M, Smith M, Averbuch S, Douglass E: Phase I study of ZD9331 on short daily intravenous bolus infusion for 5days every 3 weeks with fixed dosing recommendations. J Clin Oncol 19(5):1476–1484, 2001PubMedGoogle Scholar
  260. 260.
    Plummer R, Rees C, Hughes A, Beale P, Highley M, Trigo J, Gokul S, Judson I, Calvert H, Jackman A, Mitchell F, Smith R, Douglass E: A phase I trial of ZD 9331, a water soluble, non polyglutamatable, thymidylate synthase inhibitor. Clin Cancer Res 9(4):1313–1322, 2003PubMedGoogle Scholar
  261. 261.
    Rees C, Beale P, Trigo JM, Mitchell F, Jackman A, Smith R, Douglass E, Judson I: Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5 day continuous infusion to patients with refractory solid malignancies. Clin Cancer Res (6):2049–2055, 2003Google Scholar
  262. 262.
    de Jonge MJ, Punt CJ, Sparreboom A, Planting AS, Peters ME, van De Schraaf, Jackman A, Smith R, deMulder PH, Verweij J: Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. J Clin Oncol 20(7):1923–1931, 2002CrossRefGoogle Scholar
  263. 263.
    Sawyer MB, Ratain MJ, Bertucci D, Smith RP, Schilsky RL, Vogelzang NJ, Shulman K, Douglass EC, Fleming GF: Phase I study of an oral formulation of ZD93312 administered daily for 28 days. J Clin Oncol 21(9):1859–1865, 2003PubMedCrossRefGoogle Scholar
  264. 264.
    Petruzelka L: Phase II multicenter trial of ZD9331 monotherapy as first line treatment for gastric cancer. Anticancer Drugs 14 (Suppl 1):S7–S12, 2003Google Scholar
  265. 265.
    Hainsworth J, Vergote I, Janssens J: A review of phase II studies of ZD9331 treatment for relapsed or refractory solid tumors. Anticancer Drugs 14 (Suppl 1):S13–S19, 2003;Google Scholar
  266. 266.
    Rader JS, Clarke-Pearson D, Moore M, Carson L, Holloway R, Kao MS, Wiznitzer I, Douglass EC: A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer. Gynecol Oncol 91(2): 318–325, 2003PubMedCrossRefGoogle Scholar
  267. 267.
    Schulz J, Keller A, Canfield V, Parker G, Douglass E: ZD9331 as second or third line therapy in patients with advanced colorectal cancer: A phase II multicenter trial. Am J Clin Oncol 27(4):337–342, 2004PubMedCrossRefGoogle Scholar
  268. 268.
    Benson A 3rd, Poplin E, Vergote I: ZD9331 in combination with topotecan: Phase I and II experience. Anticancer Drugs 14 (Suppl 1):S21–S27, 2003Google Scholar
  269. 269.
    Smith D, Gallagher N: A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. Eur J Cancer 39(10):1377, 2003CrossRefGoogle Scholar
  270. 270.
    Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M: Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and or metastatic pancreatic carcinoma: A prospective randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer 94(4):902–910, 2002PubMedCrossRefGoogle Scholar
  271. 271.
    Moore MJ, Hamm J, Dancey J Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L; National Cancer Institute of Canada Clinical Trials Group: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21(17):3296–302, 2003PubMedCrossRefGoogle Scholar
  272. 272.
    Webber SE, Bleckman TM, Attard J, Deal JG, Kathardekar V, Welsh KM, Webber S, Janson CA, Matthews DA, Smith WW: Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5-substituted quinazolines. J Med Chem 36:733–746, 1993PubMedCrossRefGoogle Scholar
  273. 273.
    Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV: AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother and Pharmacol 37:509–517, 1996CrossRefGoogle Scholar
  274. 274.
    Rafi I, Taylor GA, Calvete JA, Boddy AV, Balmanno K, Bailey N, Lind M, Calvert AH, Webber S, Jackson RC: Clinical pharmacokinetic and pharmacodynamic studies with the non classical antifolate thymidylate synthase inhibitor 3, 4 dihydro-2-amino-6-methyl-4-oxo5-(-4-pyridylthio)-quinazolone dichloride (AG337) given by 24 hour continuous infusion. Clin Cancer Res 1:1275–1284, 1995PubMedGoogle Scholar
  275. 275.
    Hughes AN, Rafi I, Griffin RJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV: Phase I studies with the non classical antifolate nolatrexed dihydrochloride (AG337, Thymitaq) administered orally for 5 days. Clin Can Res 5:111–118, 1999Google Scholar
  276. 276.
    Creaven PJ, Pendyala L, Meropol NJ, Clendeninn NJ, Wu EY, Loewen GM, Proefrock A, Johnston A, Dixon M: Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10 day continuous infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol 41:167–170, 1998PubMedCrossRefGoogle Scholar
  277. 277.
    Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH: Preclinical and phase I clinical studies with the non-classical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol 16:1131–1141, 1998PubMedGoogle Scholar
  278. 278.
    Jodrell DI, Bowman A, Rye R, Byrne B, Boddy A, Rafi I, Taylor GA, Johnston A, Clendeninn NJ: A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10 day oral administration. Br J Cancer 79(5–6):915–920, 1999PubMedCrossRefGoogle Scholar
  279. 279.
    Hughes A, Calvert AH: Preclinical and clinical studies with the novel thymidylate synthase inhibitor nolatrexed dihydrochloride (Thymitaq, AG337). In: Jackman AL (ed) Anticancer Drug Development Guide: Antifolate Drugs in Cancer Therapy. Humana Press, 1999, pp. 229–241Google Scholar
  280. 280.
    Mani S, Rosen L, Bennet P, Dancey J, Conner S, Johnston A, Clendeninn N: A phase II trial of nolatrexed dihydrochloride (Thymitaq, AG337) in patients with advanced hepatocellular carcinoma. Abstract. In: Proc 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy: 1998, p 619Google Scholar
  281. 281.
    Stuart K, Tessitore J, Rudy J, Clendennin N, Johnston A: A phase II trial of nolatrexed dichloride in patients with advanced hepatocellular carcinoma. Cancer 86(3):410–414, 1999PubMedCrossRefGoogle Scholar
  282. 282.
    Mok TS, Leung TW, Lee SD, Chao Y, Chan AT, Huang A, Lui MC, Yeo W, Chak K, Johnston A, Johnson P: A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 44(4):307–311, 1999PubMedCrossRefGoogle Scholar
  283. 283.
    Pivot X, Wadler S, Kelly C, Ruxer R, Tortochaux J, Stern J, Belpomme D, Humblet Y, Domenge C, Clendennin N, Johnston A, Penning C, Schneider M: Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer. Ann Oncol 12(11):1595–1599, 2001PubMedCrossRefGoogle Scholar
  284. 284.
    van Triest B, Pinedo HM, Telleman F, van der Wilt CL, Jansen G, Peters GJ: Cross-resistance to antifolates in multidrug resistant cell lines with P glycoprotein or multidrug resistance protein expression. Biochem Pharmacol 53:1855–1866, 1997PubMedCrossRefGoogle Scholar
  285. 285.
    Tong Y, Liu-Chen X, Ercikan-Abali EA, Zhao SC, Banerjee, Maley F, Bertino JR: Probing the folate binding site of human thymidylate synthase by site directed mutagenesis. Generation of mutants that confer resistance to raltitrexed, Thymitaq, and BW184U89. J Biol Chem 273:31209–31214, 1998PubMedCrossRefGoogle Scholar
  286. 286.
    Wang X, Shen F, Freisheim JH, Gentry LE, Ratnam M: Differential sterospecificities and affinities of folate receptor isoforms for folate compounds and antifolates. Biochem Pharmacol 44:188–1901, 1992CrossRefGoogle Scholar
  287. 287.
    Habeck LL, Leitner TA, Shackleford KA, Gossett LS, Schultz RM, Andis SL, Shih C, Grindey GB, Mendelsohn LG: A novel class of monglutamated antifolates exhibits tight binding inhibition of human glycinamide ribonucleotide formyltransferase and potent activity against solid tumors. Cancer Res 54:1021–1026, 1994PubMedGoogle Scholar
  288. 288.
    Grindey GB, Alati T, Lantz R, Pohland R, Shih C: Role of dietary folic acid in blocking the toxicity but not the antitumor activity of lometrexol. Abstract. In: Proc Am Assoc Can Res 32:1921, 1991Google Scholar
  289. 289.
    Grindey GB, Alati T, Lantz R, Pohland R, Shih C: Role of dietary folic acid in blocking the toxicity but not the antitumor activity of lometrexol (DDATHF). Abstract. In: Proc NCI-EORTC Symposium on New Drugs in Cancer Therapy: 1992, p 216Google Scholar
  290. 290.
    Pohland RC, Alati T, Lantz RJ, Grindey GB: Whole body autoradiographic disposition and plasma pharmacokinetics of 5, 10-dideazatetrahydrofolic acid in mice fed folic acid deficient or regular diets. J Pharm Sci 83:1396–1399, 1994PubMedCrossRefGoogle Scholar
  291. 291.
    Wedge SR, Laohavinij S, Taylor GA, Boddy A, Calvert AH, Newell DR: Clinical pharmacokinetics of the antipurine antifolate (6R) -5, 10-dideazatetrahydrofolic acid (lometrexol) administered with an oral folic acid supplement. Clin Cancer Res 1:1479–1486, 1995PubMedGoogle Scholar
  292. 292.
    Nelson R, Butler F, Dugan W Jr, Davis-Land M, Stone M, Dyke R: Phase I clinical trial of LY 264618 (Dideazatetrahydrofolic acid: DDATHF). Abstract. In: Proc Am Soc Clin Oncol 9:76, 1990Google Scholar
  293. 293.
    Laohavinij S, Wedge SR, Lind MJ, Bailey N, Humphreys A, Proctor M, Chapman F, Simmons D, Oakley A, Robson L, Gumbrell L, Taylor GA, Thomas HD, Boddy A, Newell DR, Calvert AH: A phase I study of the antipurine antifolate lometrexol (DDATHF). Invest New Drugs 14:325–335, 1996PubMedCrossRefGoogle Scholar
  294. 294.
    Muggia FM, Synold TW, Newman EM, Jeffers S, Leichman LP, Doroshow JH, Johnson K, Groshen S: Failure of pretreatment with intravenous folic acid to alter the cumulative hematologic toxiology of lometrexol. J Natl Cancer Inst 88:495–496, 1996CrossRefGoogle Scholar
  295. 295.
    Budman DR, Johnson R, Barile B, Bowsher RR, Vinciguerra V, Allen SL, Kolitz J, Ernest CS 2nd, Kreis W, Zervos P, Walling J: Phase I and pharmacokinetic study of LY309887: A specific inhibitor of purine biosynthesis. Cancer Chemother Pharmacol 47(6):525–531, 2001Google Scholar
  296. 296.
    Ayelsworth C, Baker SD, Stephenson J, Monroe P, Sanchez I, Walling J, Johnson R, Von Hoff D, Rowinsky E: Phase I and pharmacokinetic (pk) study of the glycinamide ribonucleotide formyltransferase (GARFT) inhibitor LY309887 as a bolus every 3 weeks with folic acid (FA). Abstract. In: Proc Am Soc Clin Oncol 17:865, 1998Google Scholar
  297. 297.
    Halford S, Harper P, Highley M, Lind M, Calvert AH, Johnson R, Walling J: A Phase I and pharmacokinetic study of LY309887 given ever 3 weeks with folic acid supplementation. Abstract. In: Proc Am Soc Clin Oncol 18:652, 1999Google Scholar
  298. 298.
    Roberts JD, Shibata S, Spicer S, Spicer DV, McLeod DL, Tombes MB, Kyle B, Carroll M, Sheedy B, Collier MA, Pithavala YK, Paradiso LJ, Clendennin NJ: Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks. Cancer Chemother Pharmacol 45(5):423–427, 2000PubMedCrossRefGoogle Scholar
  299. 299.
    Bissett D, McLeod HL, Sheedy B, Collier M, Pithavala Y, Paradiso L, Pitsiladis M, Cassidy J: Phase I dose escalation and pharmacokinetic study of a novel folate analogue AG2034. Br J Cancer 84(3):308–312, 2001PubMedCrossRefGoogle Scholar
  300. 300.
    McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, Shibata S, Spicer D, Bissett D, Pithavala YK, Collier MA, Paradiso LJ, Roberts JD: Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG 2034. Clin Cancer Res 6(7):2677–2684, 2000PubMedGoogle Scholar
  301. 301.
    Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG: A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[2-92-amino-3, 4-dihydrox-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethylbenzoyl]-L-glutamic acid. J Med Chem 35:4450-4454, 1992PubMedCrossRefGoogle Scholar
  302. 302.
    Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz RM: LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate requiring enzymes. Cancer Res 57:1116–1123, 1997PubMedGoogle Scholar
  303. 303.
    Schultz RM, Patel VF, Worzalla JF, Shih C: Role of thymidylate synthase in the antitumor activity of the multitargeted antifolate, LY231514. Anticancer Res 19:437–443, 1999PubMedGoogle Scholar
  304. 304.
    Chen VJ, Bewley JR, Andis SL, Schultz RM, Iversen PW, Shih C, Mendelsohn LG, Seitz DE, Tonkinson JL: Preclinical cellular pharmacology of LY231514 (MTA): A comparison with methotrexate, LY309887 and raltitrexed for the effects on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Br J Cancer 78:27–34, 1998PubMedGoogle Scholar
  305. 305.
    Rinaldi DA, Burris HA, Dorr FA, Woodworth JR, Kuhn JG, Eckardt JR, Rodriguez G, Corso SW, Fields SM, Langley C: Initial phase I evaluation of the thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13:2842–2850, 1995PubMedGoogle Scholar
  306. 306.
    McDonald AC, Vasey PA, Adams L, Walling J, Woodworth JR, Abrahams T, McCarthy S, Bailey NP, Siddiqui N, Lind MJ, Calvert AH, Twelves CJ, Cassidy J, Kaye SB: A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4:605–610, 1998PubMedGoogle Scholar
  307. 307.
    Rinaldi DA, Kuhn JG, Burris HA, Dorr FA, Rodriguez G, Eckhardt SG, Jones S, Woodworth JR, Baker S, Langley C, Mascorro D, Abrahams T, Von Hoff DD: A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44(5):372–380, 1999CrossRefPubMedGoogle Scholar
  308. 308.
    Postmus PE, Green MR: Overview of MTA in the treatment of non-small cell lung cancer. Seminars in Oncol 26:31–36, 1999Google Scholar
  309. 309.
    Calvert AH, Walling JM: Clinical studies with MTA. Br J Cancer 78 suppl 3:35–40, 1998Google Scholar
  310. 310.
    Rusthoven JJ, Eisenhauer E, Butts C, Gregg R, Dancey J, Fisher B, Iglesias J: Multitargeted antifolate LY231514 as first line chemotherapy for patients with advanced non small cell lung cancer: A phase II study. National Institute of Canada Clinical Trials Group J Clin Oncol 17(4):1194, 1999Google Scholar
  311. 311.
    Smit EF, Mattson K, von Pawel J, Manegold C, Clarke S, Postmus PE: ALIMTA (pemetrexed disodium) as a secondline treatment of non small cell lung cancer: A phase II study. Ann Oncol 14(3):455–60, 2003PubMedCrossRefGoogle Scholar
  312. 312.
    Clarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, Ackland SP: Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy naïve patients with advanced non small cell lung cancer. Ann Oncol 13(5):737–741, 2002PubMedCrossRefGoogle Scholar
  313. 313.
    Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr: Randomized phase III trial of pemetrexed versus docetaxel in patients with non small cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589–1597, 2004PubMedCrossRefGoogle Scholar
  314. 314.
    Treat J, McCleod M, Mintzer D, Christiansen N, Bonomi P, Monberg M, Taylor L, Obasaju C: Pemetrexed plus gemcitabine as front line therapy for patients with advanced stage non-small cell lung cancer. Abstract. In: Proc Am Soc Clin Oncol 23:7130, 2004Google Scholar
  315. 315.
    Shepherd FA, Dancey J, Arnold A, Neville A, Rusthoven J, Johnson RD, Fisher B, Eisenhauer E: Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first line therapy in patients with non small cell lung carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 92(3):595–600, 2001PubMedCrossRefGoogle Scholar
  316. 316.
    Monnerat C, Le Chevalier T, Kelly K, Obasaju CK, Brahmer J, Novello S, Nakamura T, Liepa AM, Bozec L, Bunn PA, Ettinger D: Phase II study of pemetrexed gemcitabine combination in patients with advanced stage non small cell lung cancer. Clin Cancer Res. 10(16):5439–5446, 2004PubMedCrossRefGoogle Scholar
  317. 317.
    Socinski MA, Weissman C, Hart LL, Choksi JK, Holladay C, Prager D, Obasaju CK: Randomized phase II trial of pemetrexed with either cisplatin or carboplatin in extensive stage small cell lung cancer. Abstract. In: Proc Am Soc Clin Oncol 23:7204, 2004Google Scholar
  318. 318.
    Scagliotti G, Kortsik C, Castellano D, Dark G, Price A, Rosell R, Manegold C, Kayitalire L, Paul S, Blatter J. Phase II randomized study of pemetrexed + carboplatin or oxaliplatin as front line chemotherapy in patients with locally advanced or metastatic non small cell lung cancer. Abstract. Proc Am Soc Clin Oncol 22:2513, 2003Google Scholar
  319. 319.
    Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, Burris H, Gatzemeier U, Blatter J, Symanowski JT, Rusthoven JJ: Phase II study of pemetrexed with and without folic acid and vitamin B12 as frontline therapy in malignant pleural mesothelioma. J Clin Oncol 21(8):1556–1561, 2003PubMedCrossRefGoogle Scholar
  320. 320.
    Janne PA, Obasaju C, Simon G, Taub R, Kelly K, Fidias P, Bloss LP, Kindler HL: A phase 2 clinical trial of pemetrexed plus gemcitabine as front-line chemotherapy for patients with malignant pleural mesothelioma. Abstract. In: Proc Am Soc Clin Oncol 23:7053, 2004Google Scholar
  321. 321.
    Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 (14):2636–2644, 2003PubMedCrossRefGoogle Scholar
  322. 322.
    Miller KD, Picus J, Blanke C, John W, Clark J, Shulman LN, Thornton D, Rowinsky E, Loehrer PJ Sr. Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer. Ann Oncol 11(1):101–103, 2000PubMedCrossRefGoogle Scholar
  323. 323.
    Kindler H, Dugan W, Hochster H, Strickland D, Jacobs A, John W J. Clinical outcome in patients (pts) with advanced pancreatic cancer treated with pemetrexed/gemcitabine. Abstract. In: Proc Am Soc Clin Oncol 21:499, 2002Google Scholar
  324. 324.
    Richards DA, Kindler HL, Oettle H, Ramanathan R, Van Laethem J-L, Peeters M, Fuchs M, John W, Arning M, Von Hoff D: A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer. Abstract. In: Proc Am Soc Clin Oncol 23:4007, 2004Google Scholar
  325. 325.
    John W, Picus J, Blanke CD, Clark JW, Schulman LN, Rowinsky EK, Thornton DE, Loehrer PJ: Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients with advanced colorectal carcinoma: Results from a phase II study. Cancer 88(8):1807–1813, 2000PubMedCrossRefGoogle Scholar
  326. 326.
    Cripps C, Burnell M, Jolivet J, Batist G, Lofters W, Dancey J, Iglesias J, Fisher B, Eisenhauer EA: Phase II study of first-line LY231514 (multitargeted antifolate) in patients with locally advanced or metastic colorectal cancer: An NCIC Clinical Trials Group study. Ann Oncol 10(10):1175–1179, 1999PubMedCrossRefGoogle Scholar
  327. 327.
    Atkins JN, Jacobs S, Wieand S, Smith R, John W, Renshaw G, Colangelo L., Geyer C Jr., Wolmark N: Pemetrexed and oxaliplatin for first line treatment of patients with advanced colorectal cancer: A phase II trial of the NSABP foundation research program. Abstract. Proc Am Soc Clin Oncol 22:1108, 2003Google Scholar
  328. 328.
    Bajetta E, Celio L, Buzzoni R, Ferrari L, Marchiano A, Martinetti A, Longarini R, Becerra C, Ilardi C, John W: Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer. Annals Oncol 14:1543–1548, 2003CrossRefGoogle Scholar
  329. 329.
    Miles DW, Smith IE, Coleman RE, Calvert AH, Lind MJ: A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer: 37(11):1366, 2001PubMedCrossRefGoogle Scholar
  330. 330.
    Martin M, Spielmann M, Namer M, duBois A, Unger C, Dodwell D, Vodvarka P, Lind M, Calvert H, Casado A, Zelek L, Lluch A, Carrasco E, Kayitalire L, Zielinski C: Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. Ann Oncol 14(8):1246–152, 2003PubMedCrossRefGoogle Scholar
  331. 331.
    Theodoulou M, Llombart A, Cruciani G, Bloch R, Campos L, Tung N, Borges V, Perry M, Rowland K, Schuster M, Kneuper-Hall R, Hudis C: Pemetrexed disodium (Alimta LY231514, MTA) in locally advanced or metastatic breast cancer (MBC) patients (pts) with prior anthracycline or anthracenedione and taxane treatment: Phase II study. Abstract. In: Proc Am Soc Clin Oncol 19:506, 2000Google Scholar
  332. 332.
    Ma CX, Steen P, Rowland KM, Niedringhaus RD, Kugler JW, Ingle JN, Perez EA, Adjei AA: A phase II study of a combination of pemetrexed (pem) and gemcitabine (Gem) in patients with metastatic breast cancer (MBC): A NCCTG study. Abstract. In: Proc Am Soc Clin Oncol 23:639, 2004Google Scholar
  333. 333.
    Pivot X, Raymond E, Laguerre B, Degardin M, Cals L, Armand JP, Lefebvre JL, Gedouin D, Ripoche V, Kayitalire L, Niyikiza C, Johnson R, Latz J, Schneider M: Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 85(5):649–655, 2001PubMedCrossRefGoogle Scholar
  334. 334.
    Paz Ares L, Tabemoro J, Moyano A, Rifa J, Alonso J, Marcuello E, Gonzalez A, Castellano D, Hermandez S, Cotes-Funes H, Doce H: Significant activity of the multitargeted antifolate MTA (LY231514) in advanced transitional cell carcinoma (TCC) of the bladder: Results of a phase II trial. Abstract. Ann Oncol 9 (suppl 4):291, 1998Google Scholar
  335. 335.
    Thodtmann R, Sauter T, Weinknecht S, Weissbach L, Blatter J, Ohnmacht U, Hanauske A: A phase II trial of pemetrexed in patients with metastatic renal cancer. Invest New Drugs 21(3):353–358, 2003PubMedCrossRefGoogle Scholar
  336. 336.
    Goedhals L, van Wijk AL: MTA (LY231514) in advanced carcinoma of the cervix. Abstract. Ann Oncol 9 (suppl 4):339P, 1998Google Scholar
  337. 337.
    Thodtmann R, Depenbrock H, Dumez H, BlatterJ, Johnson RD, Van Oosterom A, Hanauske AR: Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 17(10):3009–3016, 1999PubMedGoogle Scholar
  338. 338.
    Hughes A, Calvert P, Azzabi A, Plummer R, Johnson R, Rusthoven J, Griffin M, Fishwick K, Boddy AV, Verrill M, Calvert H: Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 20(16):3533–3544, 2002PubMedCrossRefGoogle Scholar
  339. 339.
    Wang Y, Zhao R, Chatttopadhyay S, Goldman ID: A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new generation antifolate, pemetrexed. Cancer Res 62:6434–6437, 2002PubMedGoogle Scholar
  340. 340.
    Allen RH, Stabler SP, Savage DG, Lindenbaum J: Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. The FASEB Journal Reviews 7:1344–1353, 1993Google Scholar
  341. 341.
    Niyikiza C, Baker SD, Seitz D E, Walling J M, Nelson K, Rusthoven J, Stabler S P, Paoletti P, Calvert AH, Allen R: Homocysteine and methylmalonic acid: Markers to predict and avoid toxicity from pemetrexed therapy. Molecular Cancer Therapeutics 1:545–552, 2002PubMedGoogle Scholar
  342. 342.
    Vogelzang NJ, Emri S, Boyer MJ, Gatzemeier U, Jablons D, Taub R, Paul S, Shah P, Nguyen B: Effect of folic acid and vitamin b12 supplementation on risk benefit ratio from phase III study of pemetrexed + cisplatin versus cisplatin in malignant pleural mesothelioma. Abstract. In: Proc Am Soc Clin Oncol 22:2644, 2003Google Scholar
  343. 343.
    Oberschmidt O, Eismann UH, Platzek K, Ehnert M, Blatter J, Lahn MM, Ma D, Clet N, Paoletti P, Hanauske AR: Pemetrexed: Target gene expression inhuman solid tumors correlates with chemosensitivity patterns. Abstract. In: Proc Am Soc Clin Oncol 23:3128, 2004Google Scholar
  344. 344.
    Hanauske AR: Pemetrexed: Translational research in breast cancer. Semin Oncol 29(3 Suppl 9):40–42, 2002PubMedCrossRefGoogle Scholar
  345. 345.
    Shilsky RL: Methotrexate: An effective agent for treating cancer and building careers. The polyglutamate era. Stem Cells 14:29–32, 1996Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of MedicineUniversity of BristolBristol

Personalised recommendations