New antimetabolites in preclinical and clinical development

Expert Opinion on Investigational Drugs

Volumn 5, Issue 6, 1996, Pages 637-679

  Peters, Godefridus J ^a   Ackland, Stephen P ^b  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^b NEWCASTLE MATER HOSPITAL   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000924845     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.5.6.637     Document Type: Review

References (388)

1. ELION GB: The purine path to chemotherapy. Science (1989) 244:41-47. (Pubitemid 19130741)
2. HEIDELBERGER C, CHAUDHURI NK, DANNEBERG P et al: Fhiorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature (1957) 179:663-666.
3. PETERS GJ: Antimetabolites. In: Oxford Textbook of Oncology (Volume 1, Chapter 4.8). Peckham M, Pinedo HM, Veronesi U (Eds.), Oxford University Press, Oxford, UK (1995):524-552.
4. HILLER SA, ZHUK RA, LIDAK MJ et al: Patent specification 1168391. Br. patent No. 1 (1968):391-395.
5. DE CLERCQ E: Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact Adv. Virus Res. (1993) 43:1-55.
6. KAYE SB: Gemdtabine: current status of Phase I and n trials. J. Clin. Oncol. (1994) 12:1527-1531. (Pubitemid 24244984)
7. ARNER ESJ, ERIKSSON S: Mammalian deoxyribonu-cleoside kinases. Pharmacol. Ther. (1995) 67:155-186.
8. MULLEN CA: Metabolic suicide genes in gene therapy. Pharmacol. Ther. (1994) 63:199-207. (Pubitemid 24281475)
9. WATANABE H, YAMAMOTO S, NAITO T: Clinical results of oral UFT therapy under cooperative study. Jpn. J. Cancer Chemother. (1980) 7:1588-1596. (Pubitemid 11181215)
10. OTA K, TAGUCK T, KIMURA K: Report on nationwide pooled data and cohort Investigation in UFT Phase n study. Cancer Chemother. Pharmacol. (1988) 22:333-338.
11. PETERS GJ, VAN GROENINGEN CJ: Clinical relevance of biochemical modulation of 5-fluorouraciL Ann. Oncol. (1991) 2:469-480.
12. GRANT S: Biochemical modulation of cytosine arabl-noside. Pharmacol. Ther. (1990) 48:29-44.
13. ACKLAND SP, SCHILSKY RL: High-dose methotrexate: a critical reappraisal. J. Clin. Oncol. (1987) 5:2017-2031. (Pubitemid 18010164)
14. BERTINO JR: Ode to Methotrexate. J. Clin. Oncol. (1993) 11:5-14.
15. PETERS GJ, JANSEN G: Resistance to antimetabolites. In: Principles of Antineoplastic Drug Development and Pharmacology (Chapter28). Schilsky RL, Milano GA, Ratain MJ (Eds.), Marcel Dekker, Inc., New York, USA (1996):543-585.
16. PETERS GJ, VAN DER WILT CL: Thymidylate synthase as a target in cancer chemotherapy. Biochem. Soc. Trans. (1995) 23:884-888.
17. VAN DER WILT CL, PETERS GJ: Newtargets for pyrlmidine antimetabolites for the treatment of solid tumours. 1. Thymidylate synthase. Pharmacy World Sci. (1994) 16:84-103. (Pubitemid 24142451)
18. ANTONY AC: The biological chemistry of folate receptors. Blood (1992) 79:2807-2820.
19. WESTERHOF GR, JANSEN G, VAN EMMERIK N et al: Membrane transport of natural and antifolate compounds in murine L1210 leukemia cells: role of carrier-and receptor-mediated transport systems. Cancer Res. (1991) 51:5507-5513.
20. WESTERHOF GR, SCHORNAGEL JH, KATHMANN I et al: Carrier-and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity of inhibitors of dihydrofolate reductase, thymidylate synthase, glycinamide ribonucleotide transformylase and foh/lpoh/glutamate synthetase. Mol. Pharmacol. (1995) 48:459-71.
21. MATHERLY LH: Mechanisms of receptor-mediated folate and antifolate membrane transport in cancer chemotherapy. In: Drug Transport in Antimicrobial and Anticancer Chemotherapy. Georgopapadakou NH (Ed), Marcel Dekker, New York, (1995):453-524.
22. RHEE MS, WANG Y, NAIR MG, GALIVAN J: Acquisition of resistance to antifolates by enhanced "/-glutamyl hydrolase activity. Cancer Res. (1993) 53:2227-2230. (Pubitemid 23156804)
23. NORD L D, STOLFI RL, MARTIN DS: Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue-correlation of antitumor activity with dosage and FUra incorporation into RNA. Biochem. Pharmacol. (1992) 43:2543-2549.
24. JACKMAN AL, TAYLOR GA, CALVERT AH et al: Modulation of antimetabolite effects: effects of thymidine on the efficacy of the quinazo line-based thymidylate synthase inhibitor, CB3717. Biochem. Pharmacol. (1984) 33:3269-3275. (Pubitemid 14023263)
25. TRAUTTW: Physiological concentrations of purines and pyrimidines. Mol. CellBiochem. (1994) 140:1-22.
26. JACKMAN AL, TAYLOR GA, GIBSON W et al: ICI D1694, a qulnazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of LI 210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res. (1991) 51:5579-5581.
27. JODRELL DI, NEWELL DR, MORGAN SE et al: The renal effects of N-10-propargyl-5,8-dldeazofolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694 in mice. Br. J. Cancer (1991) 64:833-838.
28. CLARKE SJ, WARD J, DE BOER M et al: Phase I study of the new thymidylate synthase inhibitor tomudex (ZD1694) in patients with advanced malignancy. Ann. Oncol. (1994) 5(Suppl. 5):132.
29. SORENSEN JM, JORDAN E, GREM JL et al: Phase I trial of ZD1694 (tomudex), a direct inhibitor of thymidylate synthase. Ann. Oncol. (1994) 5(Suppl. 5):132.
30. ZALCBERG JR, CUNNINGHAM D, VAN CUTSEM E et al: ZD1694: a novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. J. Clin. Oncol. (1996) 14:716-721. (Pubitemid 26085514)
31. SMITH IE, SPIELMANN M, BONNETERRE J et al: Tomudex (ZD1694), a new thymidylate synthase Inhibitor with antitutnour activity in breast cancer. Ann. Oncol. (1994) 5(Suppl. 5):132.
32. CUNNINGHAM D, ZALCBERG J, SMITH IE et al: Tomudex: a novel thymidylate synthase (TS) inhibitor with clinical antitumour activity in a range of solid tumours. Ann. Oncol. (1994) 5(Suppl. 8):179.
33. GORE M, EARL H, CASSIDY J et al: Phase H study of tomudex (ZD1694) in refractory ovarian carcinoma. Ann. Oncol. (1994) 5(Suppl. 5):133.
34. BURRIS H, VON HOFF D, BOWEN K et al: A Phase n trial of ZD1694, a novel thymidylate synthase Inhibitor, in patients with advanced non-small cell lung cancer. Ann. Oncol. (1994) 5(Suppl. 5):133.
35. HEAVEN R, BOWEN K, RINALDI D et al: An open Phase n trial of ZD1694. a thymidylate synthase inhibitor, in patients with advanced non-small cell lung cancer. Proc. ASCO (1994) 13:355.
36. Tomudex (ZD1694), a thymidylate synthase inhibitor: Clinical Investigators Manual. Zeneca Pharmaceuticals, Macclesfield, UK (1994).
37. CUNNINGHAM D, ZALCBERG JR, RATH U et al: 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur. J. Cancer (1995) 31A:1945-1954. (Pubitemid 26024292)
38. ACKLAND S, KUIPER CM, GARG M et al: Variable effects of the combination of tomudex (ZD1694) and cisplatin in ovarian cancer cell lines. Proc. 9th NC1-EORTC Symp. on New Drugs in Cancer Therapy (1996):87.
39. KELLAND LR, KIMBELL R, HARDCASTLE A et al.: Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines. Eur. J. Cancer (1995) 31A:918-986.
40. IZZO J, ZIELINSKI Z, CHANG YM et al: Molecular mechanisms of the synergistic sequential administration of ZD1694 (tomudex) followed by FtJRA in colon carcinoma cells. Proc. Am. Assoc. Cancer Res. (1995) 36:A2272.
41. SMID K, VAN DER WILT CL, PETERS GJ: Effects of novel antifolates on the binding of 5-fhioro-2'-deoxyurldine-5-monophosphate (FdUMP) to bacterial and human thymidylate synthase (TS). Proc. 9th NCI-EORTCSymp. on New Drugs in Cancer Therapy (1996):90.
42. JACKMAN AL, KIMBELL R, BROWN M et al. The antltu-mour activity of ZD9331 a non-polyglutamatable quina-zoline thymidylate synthase inhibitor. In: Purine and Pyrimidine Metabolism in Man. Sahota A, Taylor M (Eds.) Adv. Exp. Med. Biol. (1995) 370:185-188.
43. JACKMAN AL, AHERNE GW, KIMBELL R et al: ZD9331 a non-polyglutamatable quinazoline thymidylate syn-thase Inhibitor. Proc. Am. Assoc. Cancer Res. (1994) 35:301.
44. STEPHENS TC, SMITH MN, MCCLOSKEY ML: ZD9331 a novel non-potyglutamated thymidylate synthase inhibitor: In vivo antitumour efficacy and toxicity to normal murine tissues. Proc. Am. Assoc. CancerRes. (1994) 35:305.
45. TAYLOR EC, KUH D: A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amJno-3,4-dihy-dro-4-oxo-7H-pyrolo[2,3-d]pyrimidin-5- yl)ethyl]benzo-yl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J.Med. Chem. (1992) 35:4450-454.
46. SHIH C, GOSSETT L, GATES S, MACKELLAR W, MENDELSOHN L, SOOSE D, PATEL V, KOHLER W, RATNAM M: LY231514 and its polyglutamates exhibit potent inhibition against both human dlhydrofolate reductase (DFHR) and thymidylate synthase (TS): multiple folate enzymes inhibition. Proc. 9th NCI-EORTC Symp. on New Drugs in Cancer Therapy. Ann. Oncol. (1996) 7(Suppl. 1):85, Abstract 289.
47. RINALDI DA, BURRIS HA, DORR FA et al: Initial Phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J. Clin. Oncol. (1995) 13:2842-2850.
48. RINALDI D, BURRIS H, DORR F etal: A Phase I evaluation of LY231514 administered every 21 days, utilising the modified continual reassessment method for dose escalation. Proc. ASCO (1995) 14:474.
49. MCDONALD AC, VASEY PA, WALLING J et al: Clinical Phase I study of LY231514, a multitargeted antifolate, administered by daily x 5 q 21 schedule. Proc. 9th NCI-EORTC Symp on. New Drugs in Cancer Therapy (1996):85.
50. WEBBER SE, BLECKMAN TM, ATTARD J et al. Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J. Med. Chem. (1993). 36:733-6.
51. WEBBER S, JOHNSTON A, SHETTY B et al: Preclinical studies on AG337, a novel lipophilic thymidylate synthase inhibitor. Proc. Am. Assoc. Cancer Res. (1993) 34:273.
52. WEBBER S, BARTLETT CA, BORITZKI TJ et al. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother. Pharmacol. (1996) 37:509-517. (Pubitemid 26080147)
53. WEBBER S, JOHNSTON A, SHETTY B et al: Preclinical studies on AG337, a novel lipophilic thymidylate synthase inhibitor. Proc. Am. Assoc. Cancer Res. (1993) 34:273.
54. RAFI I, TAYLOR GA, CALVETE JA et al: Clinical pharmacokinetic and pharmacodynamic studies with the non-classical antifolate thymidylate synthase inhibitor 3,4-dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio) quinazoline dihydrochloride (AG337) given by 24-hour continuous infusion. Clin. Cancer Res. (1995) 1:1275-1284.
55. RAFI I, TAYLOR GA, CALVETE JA etal: APhase I study of the novel antifolate AG337 given by a 5-day continuous infusion. Proc. Am. Assoc. Cancer Res. (1995) 36A1433.
56. RAFI I, BODDY AV, TAYLOR JA et al: Pharmacokinetic (PK) and pharmacodynamic (PD) studies of the non-classical thymidylate synthase (TS) inhibitor AG337 given as a 5 day infusion. Proc. 9th NCI-EORTC Symp. on New Drugs in Cancer Therapy (1996):86.
57. CREAVEN PJ, PENDYALA L, MEROPOL NJ et al: Phase I and pharmacokinetic study of 3,4-dihydro-2-amino-6-methyl-4-oxo-5
58. RAFI I, BODDY AV, TAYLOR JA etal: APhase I and clinical study of the novel antifolate AG337 given by 5 day oral administration. Proc. 9th NCI-EORTC Symp. on New Drugs in Cancer Therapy (1996) :86.
59. JODRELL D, BOWMAN A, RYE R et al: A clinical Phase I, pharmacokinetic and pharmacodynamic study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (AG337) administered by 10 day oral administration. Proc. 9th NCI-EORTC Symp. on New Drugs in Cancer Therapy (1996):86.
60. CLENDENINN NJ, JOHNSTON A: Phase n trials of Thymi taq™ (AG337) in six solid tumor diseases. Proc. 9th NCI-EORTC Symp. on New Drugs in Cancer Therapy. Ann. Oncol (1996) 7(Suppl. 1):86, Abstract 296.
61. VARNEY MD, MARZONI GP, PALMER CL et al: Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase. J. Med Chem. (1992) 35:663-676.
62. CLENDENINN NJ, PETERKIN JJ, WEBBER S et al: AG-331, a 'non-classical' lipophilic thymidylate synthase inhibitor for the treatment of solid tumors. Ann. Oncol. (1994) 5(Suppl. 5):133.
63. O'CONNOR BM, WEBBER S, JACKSON RC et al: Biological activity of a novel rationally designed lipophilic thymidylate synthase inhibitor. Cancer Chemother. Pharmacol. (1994) 34:225-229. (Pubitemid 24178513)
64. GIANTONIO B, QIAN M, GALLO J et al.: Phase I trial of AG-331 as a 5-day continuous infusion. Proc.ASCO(.1995) 14:480.
65. DUCH DS, BANKS S, DEV IK et al: Biochemical and cellular pharmacology of 1843U89, a novel benzoqui-nazoline Inhibitor of thymidylate synthase. Cancer Res. (1993) 53:810-818. (Pubitemid 23077867)
66. FERONE R, HANLON MH, WATERS KA et al: Influence of intracellular poh/glutamation on die cytotoxicity of the thymidylate synthase inhibitor 1843U89. Proc. Am. Assoc. Cancer Res. (1993) 34:274.
67. PENDERGAST W, DICKERSON SH, JOHNSON JV el al: Benzoquinazoline inhibitors of thymidylate synthase: enzyme Inhibitory activity and cytotoxicity of some 3-amino and 3-mediylbenzo[f)quinazolin-l(2H)ones. J. Med. Chem. (1993) 36:2279-2291. (Pubitemid 23262459)
68. BANKS SD, WATERS, KA, BARRETT IX et al: Destruction of WiOr multicellular tumor spheroids with die novel thymidylate synthase inhibitor 1843U89. Cancer Chemother. Pharmacol. (1994) 36:455459.
69. WILSON HR, HEATH LS, KNICK VC et al: In vivo antltu-mour activity of 1943U89, a new antifolate thymidylate synthase inhibitor. Proc. Am. Assoc. Cancer Res. (1992) 33:407.
70. SMITH GK, AMYX H, BIGLEY JW et al: 1843U89, a noncompetitive thymidylate synthase Inhibitor with novel potential for enhanced antitumor selectivity via combination with folic acid. Proc. Am. Assoc. Cancer Res. (1996)37:651.
71. BURRIS HA, KISOR DF, SMETZER JR et al: A Phase I pharmacokinetic (PK) study of the thymidylate synthase inhibitor 1843U89 during a daily x 5 bolus administration schedule. Proc. ASCO (1996) 15:477.
72. ALLEGRA CJ, FINE RL, DRAKE JC et al: The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells: evidence for direct inhibition of purine synthesis. J. Biol Chem. (1986) 261:6478-6485. (Pubitemid 17204161)
73. GOLDIN A, VENDITTI JM, KLINE L et al: Eradication of leukemic cells (L1210) by methotrexate and meuiotr-exate plus dtrovorum factor. Nature (1966) 212:1548-1550.
74. CURT CA, CARNEY DN, COWAN KH et al.: Unstable meuiotrexate resistance in human small cell carcinoma is associated with double minute chromosomes. New Engl. J. Med. (1983) 308:199-202. (Pubitemid 13171140)
75. LI WW, LIN JT, TONG WP et al: Mechanisms of natural resistance to antlfolates in human soft tissue sarcomas. Cancer Res. (1992) 52:1434-1438.
76. SIROTNAK FM: Determinants of resistance to antifolates: biochemical phenotypes, nieir frequency of occurrence and circumvention. Natl Cancer Inst. Monogr. (1987) 5:27-35. (Pubitemid 18000392)
77. MARSHALL JL, DELAP RJ: Clinical pharmacokinetics and pharmacology of trimetrexate. Clin. Pharm. (1994) 26:190-200. (Pubitemid 24081624)
78. FRY DW, BESSERER JA: Characterization of trimetrexate transport in human lymphoblastoid cells and development of impaired Influx as a mechanism of resistance to lipophilic antifolates. Cancer Res. (1988) 48:6986-6991. (Pubitemid 19013969)
79. ARKIN H, OHNUMA T, KAMEN BA et al: Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate. Cancer Res. (1989) 49:6556-6561. (Pubitemid 20008786)
80. ROGERS P, ALLEGRA CJ, MURPHY RF etal: Bioavailability of oral trimetrexate in patients 'with acquired immunodeficiency syndrome. Antimicrob. Agents Chemother. (1988) 32:324-326. (Pubitemid 18063556)
81. WEIS RB, JAMES WD, MAJOR WB et al.: Skin reactions induced by trimetrexate, an analog of methotrexate. Invest. New Drugs (1986) 4:159-163. (Pubitemid 16087369)
82. DUCH DS, EDELSTEIN MP, NICHOL CA: Inhibition of histamine metabolic enzymes and elevation of histamine levels in tissues by lipid soluble anticancer folate antagonists. Mol Pharmacol. (1980) 18:100-104. (Pubitemid 10093093)
83. ROBERT F: Trimetrexate as a single agent in patients with advanced head and neck cancer. Semin. Oncol. (1988) 15:22-26.
84. MAROUN J: Clinical response to trimetrexate as sole therapy for non small cell lung cancer. Semin. Oncol. (1988) 15:17-21.
85. FOSSELLA FV, WINN RJ, HOLOYE PY et al: Phase H trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma. Invest. New Drugs (1992) 10:331-335. (Pubitemid 23008984)
86. WITTE RS, ELSON P, KHANDAKAR J et al: An Eastern Cooperative Oncology Group Phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma. Cancer(1994) 73:688-691.
87. GESME DH, JETT JR, SCHREFFLER DD etal: A randomized Phase n trial of amonafide or trimetrexate in patients with advanced non-small cell lung cancer: a trial of the North Central Cancer Treatment Group. Cancer (1993) 71:2723-2726. (Pubitemid 23120045)
88. KRIS MG, DAQUISITO RW, GRALLA RJ et al: Phase D trial of trimetrexate In patients 'with stage n and IV non-small-cell lung cancer. Am J. Clin. Oncol. (1989) 12:24-26. (Pubitemid 19037246)
89. ALBERTS AS, FALKSON G, BADATA M et al: Trimetrexate in advanced carcinoma of die esophagus. Invest New Drugs (1988) 6:319-321. (Pubitemid 19010331)
90. SHER HI, CURLEY T, GELLER N et al: Trimetrexate in prostatic cancer: preliminary observations on die use of prostate-specific antigen and acid phosphatase as a marker in measurable hormone-refractory disease. . J. Clin. Oncol. (1990) 8:1830-1838. (Pubitemid 20382345)
91. WITTE RS, YEAP BY, TRUMP DL Trimetrexate in advanced hormone-refractory prostate cancer. An ECOG Phase H trial Invest. New Drugs (1994) 12:255-258. (Pubitemid 24376412)
92. EISENHAUER EA, WIERZBICKI R, KNOWLING M et al: Phase n trials of trimetrexate in advanced adult soft tissue sarcoma. Ann. Oncol. (1991) 2:689-690.
93. LICHT JD, GONIN R, ANTMAN KH: Phase H trial of trlmetrexate in patients with advanced soft-tissue sarcoma. Cancer Chemother. Pharmacol. (1991) 28:223-225.
94. LEIBY JM: Trlmetrexate: a Phase n study in previously treated patients with metastatic breast cancer. Semin. Oncol. (1988) 15:27-31.
95. DAWSON NA, COSTANZA ME, KORZUN AH et at.: Trlmetrexate in untreated and previously treated patients with metastatic breast cancer: a Cancer and Leukemia Group B study. Med. Pediatr. Oncol. (1991) 19:283-288.
96. VOGELZANG NJ, WEISMAN LB, HERNDON JE et al: Trlmetrexate In malignant mesothelioma: a Cancer and Leukemia Group B Phase n study. J. Clin. Oncol. (1994) 12:1436-1442. (Pubitemid 24206243)
97. HANTEL A, TANGEN CM, MACDONALD JS et al: Phase H trial of trlmetrexate in untreated advanced gastric car-cimona: a Southwest Oncology Group study. Invest. New Drugs (1994) 12:155-157. (Pubitemid 24350656)
98. ASBURY RF, CNAAN A, HALLER D: Eastern Coopreative Oncology Group (ECOG) Phase n study of trlmetrexate In metastatic gastric cancer. Proc. ASCO (1990) 9:126.
99. WITTE RS, ELSON P, BRYAN GT et al: Trlmetrexate in advanced renal cell carcinoma. Invest. New Drugs (1992) 10:51-54.
100. WEISS GR, LIU PY, O'SULLIVAN J et al: A randomized Phase II trial of trlmetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial. Gynecol. Oncol. (1992) 45:303-306.
101. CARLSON RW, DOROSHOW JH, ODUJINRIN OO et al: Trlmetrexate In locally advanced or metastatic adenocarcinoma of the pancreas: a Phase n study of the Northern California Oncology Group. Invest. New Drugs (1990) 8:387-390.
102. AJANIJA, ABBRUZZESE JL, FAINTUCH JS et al.: A Phase H study of trlmetrexate therapy for metastatic colorectal carcinoma. Cancer Invest. (1990) 8:619-621.
103. ODJUNRIN O, GOLDBERG D, DOROSHOW J et al: Treatment of metastatic malignant melanoma with trlmetrexate: a Phase n study. Med. Pediatr. Oncol. (1990) 18:49-52. (Pubitemid 20032810)
104. ISCOE NA, EISENHAUER EA, BODURTHA AJ et al: Phase n study of trlmetrexate In malignant melanoma: a NCI of Canada Clinical Trials Group study. Invest. New Drugs (1990) 8:121-123. (Pubitemid 20087257)
105. CAINCROSS JG, EISENHAUER EA, MACDONALD DR et al: Phase II study of trimetrexate in recurrent anaplastic glioma: a NCI of Canada Clinical Trials Group study. Can. J. Neurol. Sci. (1990) 17:21-23. (Pubitemid 20101019)
106. KHERADPOUR A, BERMAN E, GOKER E et al: A Phase H study of continuous Infusion of trimetrexate in patients with refractory acute leukemia. Cancer Invest. (1995) 13:3640.
107. ROMANINI A, LI WW, COLOFIOR JR et al: Leucovorin enhances cytotoxicity of trimetrexate/Quorouracil, but not methotrexate/fluorouracil in CCRF-CEM cells. J. Natl. Cancer Inst. (1992) 84:1033-1038.
108. CONTIJA, KEMENY N, SEITER K et al: Trial of sequential trimetrexate, fluorouracil and high-dose leucovorin in previously treated patients wfth gastrointestinal cancer. J. Clin. Oncol. (1994) 12:695-700. (Pubitemid 24110907)
109. BLANKE C, KASIMIS B, KURMAN M, CAPIZZI R, SCHEIN P: Trimetrexate (TMTX) modulation of 5-fhiorouracil/leu-covorln (5-FU/LV) for advanced colorectal cancer. Proc. 9th NCI-EORTC Symp. on New Cancer Drugs. Ann. Oncol. (1996) 7(Suppl. 1):69, Abstract 233.
110. SCHMID FA, SIROTNAK FM, OTTER GM, DEGRAW JI: New folate analogues of 10-deaza-aminopterin 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. (1985) 69:551-553. (Pubitemid 15031407)
111. SIROTNAK FM, DEGRAW JI, MOCCIO DM etal: New folate analogs of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties. Cancer Chemother. Pharmacol.(1984) 12:18-25. (Pubitemid 14216733)
112. SCHMID FA, SIROTNAK FM, OTTER GM et al: Combination chemotherapy with a new folate analog: activity of 10-ethyl-lO-deaza-aminopterin compared to methotrexate with 5-fluorouracU and alkylating agents against advanced metastatic disease in murine tumor models. Cancer Treat. Rep. (1987) 71:727-732.
113. KRIS MG, KNIAHAN JJ, GRALLA RJ etal: Phase H trial and clinical pharmacological evaluation of 10-etiryl-lO-deazaaminopterin in adult patients 'with advanced cancer. Cancer Res. (1988) 48:5573-5579.
114. GRANT SC, KRIS MG, YOUNG CW et al: Edatrexate, an antifolate with antitumor activity: a review. Cancer Invest. (1993) 11:3645.
115. KUEBLER JP, BENEDETTI J, SCHULLER DE et al: Phase n study of edatrexate In advanced head and neck cancer: a Southwest Oncology Group study. Invest. New Drugs (1994) 12:341-344.
116. GREEN MD, SHERMAN P, ZALCBERG J: Phase DJ study of 10-Edam in patients with squamous cell cancer of the head and neck, previously untreated with chemotherapy. Invest. New Drugs (1992) 10:21-34.
117. SCHORNAGEL JH, VERWEIJ J, MULDER PH et al. A Phase II trial of 10-ethyl-lO-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. (1992) 3:223-226.
118. FURUSE K, TAGUCHI T, FURUE H et al: Early Phase n study of edatrexate (10-Edam) in patients with malignant tumors-10-Edam Cooperative Clincal Study Group. J.Jpn. Soc. CancerTher. (1995) 30:1673-1683.
119. VANDENBERG TA, PRITCHARD KI, EISENHAUER EA et al: 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. (1993) 11:1241-1244. (Pubitemid 23199125)
120. SCHORNAGEL JH, VAN DER VEGT S, VERWEIJ J etal: Phase D study of edatrexate in chemotherapy-naive patients with metastatic breast cancer. Ann. Oncol. (1992) 3:549-552.
121. BOOSER DJ, DYE CA, CLEMENTS SB et al: Edatrexate (10-EDAM) for metastatic breast cancer: Phase B study. Proc. ASCO (1994) 13:109.
122. PEREZ EA, WHITALL D, HESKETH PJ et al: Phase I trial of biweekly edatrexate in metastatic breast cancer. Proc. ASCO (1994) 13:59.
123. SHUM KY, KRIS MG, GRALLA RJ et al: Phase n study of 10-ethyl-lO-deaza- aminopterin in patients with stage m and IV non-small-cell lung cancer. J. Clin, Oncol. (1988) 6:446-50. (Pubitemid 18090690)
124. SOUHAMI RL, RUDD RM, SPIRO SG et al: Phase H study of edatrexate in stage m and IV non-small-cell lung cancer. Cancer Chemother. Pharmacol (1992) 30:465-468.
125. LEEJS, LIBSHITZ HI, MURPHY WK et al: Phase H study of 10-ethyl-lO-deaza-aminopterin in patients with stage mB or IV non-small-cell lung cancer. Invest. New Drugs (1990) 8:299-304. (Pubitemid 20267729)
126. YOKOYAMA A, KNIAMERI K, KURITA Y et al: Phase n study of 10-EDAM in non small cell lung cancer. Proc. ASCO (1994) 13:358.
127. CASPER ES, CHRISTMAN KL, SCHWART GK et al: Edatrexate in patients with soft tissue sarcoma: activity in malignant fibrous histiocytoma. Cancer(1993) 72:766-770. (Pubitemid 23215262)
128. KNOWLING M, BRAMWELL V, EISENHAUEREA etal: Phase n trial of 10-EDAM in advanced soft tissue sarcoma. A study of the Canadian Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group. Ann. Oncol (1994) 5:766-768.
129. PAZDUR R, MOORE DF, BREADY B et al: Phase n trial of edatrexate in patients with advanced hepatocellular carcinoma. Ann. Oncol. (1994) 5:646-648. (Pubitemid 24283104)
130. MOORE DF, PAZDUR R, ABBRUZZESE JL et al: Phase n trial of edatrexate in patients with advanced pancreatic carcinoma. Ann. Oncol (1994) 5:286-287. (Pubitemid 24097527)
131. CASPER ES, SCHWARTZ GK, JOHNSON B et al: Phase n trial of edatrexate in patients with advanced pancreatic adenocarcinoma. Invest. New Drugs (1992) 10:313-316. (Pubitemid 23008980)
132. WEISENFELD M, JETT JR, SU JQ et al: Phase H trial of edatrexate in small cell lung cancer. Cancer (1994) 73:1189-1193. (Pubitemid 24061614)
133. KEMENY N, ISRAEL K, O'HEHIR M et al: Phase H trial of 10-EDAM in patients with advanced colorectal carcinoma. Am. J. Clin. Oncol. (1990) 13:42-44. (Pubitemid 20114558)
134. SCHULTZ PK, LIEBERTZ C, KELLY WK et al: Post-therapy change in prostate-specific antigen levels as a clinical trial endpoint in hormone-refractory prostatic cancer: a trial with 10-ethyl-oeaza-aminopterin. Urology (1994) 44:237-241.
135. VERMA S, QUIRT IC, EISENHAUER EA et al: A Phase n study of weekly edatrexate in metastatic melanoma: an NCI of Canada. Clinical Trials Group Study. Ann. Oncol. (1993) 4:254-255. (Pubitemid 23121668)
136. BROUN ER, ISEMINGERKA, BOOKMAN M: A Phase II trial of edatrexate in previously treated ovarian cancer. A Gynecologic Oncologic Group study. Am. J. Clin. Oncol. (1995) 18:164-165.
137. HUBER MH, DIMERY IW, BENNER SE et al: Phase H study of carboplatin and edatrexate (10-EDAM) with leuco-vorin rescue for patients with recurrent squamous cell carcinoma of the head and neck. Invest. New Drugs (1994) 12:327-331.
138. OTTER GM, SIROTNAK FM: Effective combination therapy of metastatic murine solid tumors-with edatrexate and the vinca alkaloids, vinblastine, navelbine and vindesine. Cancer Chemother. Pharmacol. (1994) 33:286-290. (Pubitemid 24033051)
139. KRIS MG, GRALLA FJ, POTANOVICH LM et al: Incorporat ing 10-ethyl-lO-deazaaminopterin (EDAM) into combi nation therapy with mitomycin (M) and vinblastine (V) for patients with advanced non-small cell lung cancer (NSCLC). Proc. ASCO (1989):8.
140. CHOU TC, OTTER GM, SIROTNAK FM: Schedule-dependent synergism of taxol or taxotere with edatrexate against human breast cancer cells in vitro. Cancer Chemother. Pharmacol. (1996) 37:222-228.
141. GANDARA D, EDELMAN M, SMITH G etal: Edatrexate and carboplatin In stage IV non-small cell lung cancer: Phase Q trial of the Southwest Oncology Group (SWOG). Proc. ASCO (1996) 15:397.
142. SIROTNAK FM, OTTER GM, SCHMID FA: Markedly Improved efficacy of edatrexate in a high-dose regimen with leucovorin rescue against solid tumors. Ann. Oncol. (1992) 3(Suppl. 1):193.
143. JOLIVET J, JANSEN G, PETERS GJ, PINARD M-F, SCHOR-NAGELJ: Leucovorin rescue of human cancer and bone marrow cells following edatrexate or methotrexate exposure. Biochem. Pharmacol. (1994) 47:659-665. (Pubitemid 24094270)
144. GRUNBERG SM, SPEARS CP, NATALE R et al: Phase I evaluation of high-dose edatrexate with leucovorin rescue. Proc. ASCO (1994) 13:364.
145. PISTERS KMW, TYSON LB, BERTINO JR et al. High dose edatrexate with oral leucovorin rescue: a Phase I trial. ASCO (1994) 13:364.
146. SEDWICK WD, HAMRELL M, BROWN OE et al: Metabolic inhibition by a new antlfolate, 2,4-dlamino-6-(2,5-di-methoxybenzyl)-5methylpyridol[2,3-D] pyrimld-lne(BW301U), an effective Inhibitor of human lymphoid and dlhydrofolate reductase-overproducing cell lines. Mol Pharmacol. (1982) 22:766-770. (Pubitemid 13201839)
147. DUCH DS, EDELSTEIN MP, NICHOL CA: Inhibition of histamine metabolic enzymes and elevation of histamine levels in tissues by lipid soluble anticancer folate antagonists. Mol. Pharmacol. (1980) 18:100-104. (Pubitemid 10093093)
148. ADAMSON PC, BALIS FM, MISER J et al: Pediatric Phase I trial and pharmacokinetic study of plrltrexim administered orally on a 5 day schedule. Cancer Res. (1990) 50:4464-4467. (Pubitemid 20230376)
149. ADAMSON PC, BALIS FM, MISER J et al: Pediatric Phase I trial, pharmacokinetic study, and limited sampling strategy for plrltrexim administered on a low-dose, Intermittent schedule. Cancer. Res. (1992) 52:521-524.
150. FEUN LG, ROBINSON WA, SAVARAJ N et al: Phase H trial of plrltrexim and DTIC using an alternating dose schedule in metastatic melanoma. Am. J. Clin. Oncol. (1995) 18:488-490. (Pubitemid 26004055)
151. UEN WC, HUANG AT, MENNEL R et al: A Phase H study of piritrexim in patients-with advanced squamous head and neck cancer. Cacer(1992) 69:1008-1011.
152. DEGARDIN M, DOMENGE C, CAPPELAERE P et al: A Phase U study of plrltrexim in patients with advanced squamous cell carcinoma of the head and neck. Eur. J. Cancer (1994) 30A:1044-1045. (Pubitemid 24256265)
153. DEWIT R, KAYE SB, ROBERTS JT et al: Oral piritrexim, an effective treatment for metastatic urothelial cancer. Br. J. cancer. (1993) 67:388-390. (Pubitemid 23049568)
154. CLENDENINN NJ, SAVARAJ N, BENEDETTO P et al.: Compassionate use of oral piritrexim in advanced bladder cancer: an effective drug after progression on MVAC chemotherapy. Proc. Am. Assoc. Cancer Res. (1991) 32:A1110.
155. FEUN LG, GONZALEZ R, SAVARAJ N et al:. Phase n trial of piritrexim In metastatic melanoma using intermittent low-dose administration. J. Clin. Oncol. (1991) 9:464-67.
156. DE VRIES EG, GIETSMA JA, WORKMAN P et al: APhase U and pharmacokinetic study with oral piritrexim for metastatic breast cancer. Br. J. Cancer (1995) 68:641-644.
157. SCHIESEL JD, CARABASI M, MAGILL G et al: Oral piritrexim, a Phase n study In patients with advanced soft tissue sarcoma. Invest. New Drugs (1992) 10:97-98.
158. BLEEHAN NM, NEWMAN HV, RAMPUNG RP etal: APhase n study of oral piritrexim in recurrent high-grade (m,rv) glioma. Br. J. Cancer (1995) 72:766-768.
159. VOKES EE, DIMERYIW, JACOBS CD etal: A Phase II study of piritrexim in combination with methotrexate in recurrent and metastatic head and neck cancer. Cancer (1991) 67:2253-2257.
160. BALDWIN SW, TSE A, GOSSETT LS et al: Structural features of 5,10-dideaza-5,6,7,8 tetrahydrofolate that determine inhibition of mammalian glycinamide ribonucleotide formyltransferase. Biochemistry (1991) 30 1997-2001.
161. PIZZORNO G, MOROSON BA, CASHMORE AR et al:. Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. Cancer Res. (1995) 55:566-573.
162. TSE A AND MORAN RG Control of the pofyglutamation of 5,10- dldeazatetrahydrofolate by Intracellular folate pools: a novel mechanism of resistance to antifolates. Proc. Am. Assoc. Cancer Res. (1994) 35:A1809.
163. LEHMAN NL: The stereospecific cytotoxic potency of (6R) and (6S)-5,10-dideazatetrahydrofolate correlates with cellular folylporyglutamate synthase levels. Bio-chimie (1995) 77:273-278.
164. ERBA E, SEN S, SESSA C et al.: Mechanism of cytotoxicity of 5,10-dideazatetrahydrofolic add in human ovarian carcinoma cells in vitro and modulation of the drug activity by folic or folinic acid. Br. J. Cancer (1994) 69:205-211. (Pubitemid 24046538)
165. HABECK L, WORZALLA JF, SHIH C et al: Deposition and polyglutamate distribution of l4C-lometrexol and its thiophene analogue in murine liver and C3H mammary tumor. Proc. Am. Assoc. Cancer Res. (1995) 36:A2255.
166. NELSON R, BUTLER F, DUGAN W Jr etal: Phase I clinical trial of LY264618 (dideazatetrahydrofolic acid: DDATHF). Proc. ASCO (1990) 9:76.
167. GRINDEY GB, ALATI T, SHIH C et al: Reversal of the toxicity but not the antitumor activity of lometrexol by folic acid. Proc. Am. Assoc. Cancer Res. (1991) 32:324.
168. GRINDEY GB, ALATI T, LANTZ R et al.: Role of dietary folic acid in blocking the toxicity but not the antitumor activity of lometrexol (DDATHF). Ann. Oncol. (1992) 3(Suppl. 1):162.
169. RAY MS, MUGGIA FM, LEICHMAN CG et al.: Phase I study of (6R)-5,10-dideazatetrahydrofolate: a folate anti-metabolite inhibitory to de novo purine synthesis. J. Natl. Cancerlnst. (1993) 85:1154-1159. (Pubitemid 23212282)
170. COLE JT, GRALLA RJ, KARDINAL CG et al: Lometrexol: Phase I trial of a weekly schedule of this new antifolate. Proc. Am. Assoc. Cancer Res. (1992) 33:A2468.
171. YOUNG C, CURRIE VE, MUINDI JF et al: Phase I and clinical pharmacologic study of LY264618, 5,10-dideazatetrahydrofolate. Proc. Am. Assoc. Cancer Res. (1990) 31:A1053.
172. SESSA C, DE JONG J, KERN H et al: Phase I studies of lometrexol (LY264618, DDATHF) given every 4 weeks. Ann. Oncol. (1992) 3:22.
173. YOUNG CW, CURRIE VE, MUINDI JF et al: Improved clinical tolerance of lometrexol with oral fohc add. Proc. Am. Assoc. Cancer Res. (1992) 33:A2422.
174. BAILEY N, LIND MJ, LAOHAVINIJ S etal: A dose escalation study of lometrexol (L, DDATHF) with folic add. Proc. ASCO(1996) 15:487.
175. WEDGE SR, LAOHAVINIJ S, TAYLOR GA et al.: Clinical pharmacokinetics of die antipurine antifolate (6R) 5,10-dideazatetrahydrofolic add (lometrexol) administered with an oral folic add supplement. Clin. Cancer Res. (1995) 1:1479-1486.
176. PIZZORNO G, DAVIS SJ, HARTIGAN DJ et al: Enhancement of antineoplastic activity of 5-fluorour adl in mice bearing colon 38 tumor by (6R)5,10-dldeazatetrahydro-folicacid. Biochem. Pharmacol. (1994) 47:1981-1988. (Pubitemid 24192052)
177. HABECK LL. LEITNERTA, SHACKELFORD KA etal: Anovel class of monoglutamated antifolates exhibits tight-binding inhibition of human glycinamide ribonucleotide formyltransferase and potent activity against solid tumors. Cancer Res. (1994) 54:1021-1026. (Pubitemid 24085457)
178. WORZALLA JF, RUTHERFORD PG, SELF TD et al: In vivo antitumor activity of LY309887, a new antifolate inhibitor of glycinamide ribonucleotide formyl transferase. Proc. Am. Assoc. Cancer Res. (1995) 36:A2253.
179. BORITZKITJ, BARTLETT CA, HOWLAND EF et al: Biological properties of AG2034: a new inhibitor of gb/d-namide ribonucleotide formyltransferase. Proc. Am. Assoc. Cancer Res. (1996) 37:A2628.
180. BORITZKI TJ, ZHANG C, PALMER CL et al: The gb/d-namide ribonucleotide formyltransferase inhibitor, AG2034, causes S phase arrest and cell death in tumor cells in culture. Proc. Am. Assoc. Cancer Res. (1996) 37A2459.
181. FAESSEL H, SLOCUM HK,JACKSON RC etal: Superilt vitro synergy between trimetrexate and the poh/glutamylat-able antifolates AG2034, AG2032, AG2009 and tomudex against human HCT-8 colon cells. Proc. Am. Assoc. Cancer Res. (1996) 37: A2629.
182. ALATI T, SHIH C, POHLAND RC et al: Evaluation of the mechanism of inhibition of the toxicity, but not the antitumor activity of lometrexol (DDATHF) by folic add. Proc. Am. Assoc. Cancer Res. (1992) 33A2432.
183. MOERTEL CG: Chemotherapy of gastrointestinal cancer. New Engl. J. Med. (1978) 299:1049-1052.
184. MOERTEL CG: Chemotherapy of gastrointestinal cancer. New Engl J. Med. (1994) 330:1136-1142.
185. PINEDO HM, PETERS GJ: 5-Fluorouracil: biochemistry and pharmacology. J. Clin. Oncol. (1988) 6:1653-1664.
186. SPEARS CP, GUSTAVSSON BG, MITCHELL MS et al: Thymidylate synthase inhibition in malignant tumors and normal liver of patients given Intravenous 5-fhiour-ouradL Cancer Res. (1984) 44:4144-4150. (Pubitemid 14041649)
187. SWAIN SM, LIPPMAN ME, EGAN EF etal: Fluorouracil and high-dose leucovorin in previousb/treated patients with metastatic breast cancer. J. Clin. Oncol. (1989) 7:890-899. (Pubitemid 19172462)
188. PETERS GJ, VAN DER WILT CL, VAN GROENINGEN CJ et al.\ Thymidylate synthase inhibition after administration of 5-fhiorouracil with or without leucovorin; implications for treatment with 5-fluorouracil. J. Clin. Oncol. (1994) 12:2035-2042. (Pubitemid 24356018)
189. PETERS GJ, VAN GROENINGEN CJ, LAURENSSE EJ, PINEDO HM: A comparison of 5-fluorouracil metabolism in human colorectal cancer and colon mucosa. Cancer (1991) 68:1903-1909.
190. PETERS GJ, BRAAKHUIS BJM, DE BRUIJN EA et al: Enhanced therapeutic efficacy of 5'-deoxy-5-Quorouridine in 5-fhiorouradl resistant head and neck tumours in relation to 5-fluorouracfl metabolizing enzymes. Br. J. Cancer(1989) 59:327-334. (Pubitemid 19099991)
191. LONN U, LONN S: Increased growth Inhibition and DNA lesions in human colon adenocarcinoma cells treated with methotrexate or 5-fluorodeoxy-urldine followed by calmodulin inhibitors. Cancer Res. (1988) 48:3319-3323.
192. NAGUIB FNM, EL KOUNI MH, CHA S: Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res. (1985) 45:5405-5412. (Pubitemid 16200794)
193. SPOELSTRA EC, PINEDO HM, PETERS GJ et al: Measurement of in vitro cellular pharmacokinetics of 5-fluorouracfl in human and rat cancer cell lines and rat hepatocytes using a flow-through system. Cancer Chemother. Pharmacol. (1991) 27:320-325.
194. BECK A, ETIENNE MC, CHERADAME S et al: A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumor sensitivity to fluorouracil. Eur. J. Cancer(1994) 30A:1517-1522. (Pubitemid 24343014)
195. PETERS GJ, VAN DER WELT CL, VAN GROENINGEN CJ: Predictive value of thymidylate synthase and dihydropyrimidine dehydrogenase. Eur. J. Cancer (1994) 30A: 1408-1411. (Pubitemid 24342995)
196. WOODCOCK TM, MARTIN DS, DAMIN LEM: Clinical trials with thymidine and fluorouracil: a Phase I and clinical and pharmacological evaluation. Cancer (1980) 45:1135-1143. (Pubitemid 10125123)
197. PAZDUR R, LASSERE Y, RHODES V et al: Phase H trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J. Clin. Oncol. (1994) 12:2296-2300. (Pubitemid 24346698)
198. SPECTOR T, PORTER DJT, NELSON DJ et al.: 5-Ethynylu-racil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drugs Future (1994) 19:565-571. (Pubitemid 24247872)
199. SHIRASAKA T, FUKUSHIMA M, SHIMAMOTO Y, KIMURA K: Preclinical Studies on S-l, a New Oral Tegafur plus Modulators: Optimal Molar Ratio and Antitumor Activity. Recent Advances in Chemother. Proc. 18th Int. Congr. Chemotherapy (1993)527.
200. FUJITA H, OKAMOTO M, TAKAO A, MATSUSHIMA E, SHIRASAKA T: Preclinical studies of s-l, a new oral tegafur, phis modulators: pharmacokinetics. Recent Advances in Chemother. Proc 18th Int Congr Chemotherapy (1993):928-929.
201. DE BRUIJN EA, VAN OOSTEROM AT, TJADEN UR: Site-specific delivery of 5-fluorouracil with 5'-deoxy-5-fluorouridine. Reg. Cancer Treatment (1989) 2:61-76.
202. ALBERTO P, MERMILLOD B, GERMANO G etal.: A randomized comparison of doxlfluridine and fluorouracil in colorectal carcinoma. Eur. J. Cancer Clin. Oncol. (1988) 24:559-563. (Pubitemid 18071296)
203. VAN DER WILT CL, PINEDO HM, CLOOS J et al: Effect of folinic acid on 5-fluorouracil activity and expression of thymidylate synthase. Sem. Oncology (1992) 19(Suppl. 3): 16-25.
204. DE CESARE M, PRATESIG, DE BRAUD, F etal.: Remarkable antitumor activity of 5'-deoxy-5-fhiorouridine In human colorectal tumor xenografts. Anticancer Res. (1994) 14:549-554. (Pubitemid 24176802)
205. MIWA M, ISHKAWA T, EDA H et al: Comparative studies on the antitumor and immunosuppressive effects of the new fluorouracil derivative ij4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and its parent drug 5'-deoxy-5-fluorourldine. Chem. Pharm. Bull. (1990) 38:998-1003. (Pubitemid 20185813)
206. NINOMIYA Y, MIWA M, EDA H et al: Comparative Antitumor Activity and Intestinal Toxicity of 5'-Deoxy-5-fluorouridine and Its Prodrug Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine. Jpn. J. Cancer Res. (1990) 81:188-195. (Pubitemid 20092572)
207. HUGHES M, PLANTING A, TWELVES C etal: A Phase I study of intermittent twice dally oral therapy with caped-tablne in patients with advanced and/or metastatic solid cancer. Proc. 9th NCI-EORTC Symp. Ann. Oncol. (1996) 7(Suppl. 1):87, [Abstract 297].
208. MEROPOL NG, BUDMAN DR, CREAVEN PJ, et al: A Phase I study of continuous twice daily treatment with cape-citabine in patients with advanced and/or metastatic solid tumors. Proc. 9th NCI-EORTC Symp. Ann. Oncol. (1996) 7(Suppl. 1):87, [Abstract 298].
209. TAGUCHI T, ISHITANI K, SAITOH K et al: A Japanese Phase I study of continuous twice daily treatment with capedtablne in patients with advanced and/or metastatic solid tumors [Abstract 299]. Proc 9th NCI-EORTC Symp: Ann. Oncol. (1996) 7(Suppl. 1):87.
210. FRIEDMAN MA, IGNOFFO RJ: A review ofthe United States Hiniral experience of the fluoropyrlmidlne, Ftorafur (NSC-148958). Cancer Treat. Rev. (1980) 7:205-213. (Pubitemid 11115826)
211. NAGUIB FNM, EL KOUNI MH, CHA S: Structure-activity relationship of ligands of dihydrouradldehydrogenase from mouse liver. Biochem. Pharmacol. (1989) 38:1471-1480. (Pubitemid 19123340)
212. IKENAKA K, SHIRASAKA T, KITANO S, FUJII S: Effect of uracil on metabolism of 5-fluorouracil in vitro. Gann. (1979) 70:353-359. (Pubitemid 9243954)
213. UNEMI N, TAKEDA S, TAJIMA K et al.: Studies on combi nation therapy with l-(tetrahydro-2 furanyl)-5-fhiorour acul phis uracil. I. Effect of coadministration of uracil on the antitumor activity of l (Pubitemid 11124964)
214. TAGUCHI T, NAKANO Y, FUJII S et al: Determination of 5-fluorouracil levels In tumors, blood, and other tissues. Jpn.J. Cancer Chemother. (1978) 5:1167-1172.
215. FUJII S. IKENADA K, FUKUSHIMA M etal: Effect of uracil and Its derivatives on antitumor activity of 5-Quorouracll and l5-fluorouracll Gann. (1978) 69:763-772. (Pubitemid 9081584)
216. CAO S, FRANK C, SHIRASAKA T, RUSTUM YM: 5-FluorouracH prodrug: role of anabolic and catabolic pathway modulation in therapy of colorectal cancer. Clin. Cancer Res. (1995) 1:839-845.
217. HO DH, COVINGTON WP, PAZDUR R et al: Clinical pharmacology of combined oral uracil and ftorafur. Drug Metab. Dispos. (1992) 20:936-940.
218. TSENG C-C, NIO Y, TSUBONO M et al. The role of additional chemotherapy with oral uft in intravenous combination chemotherapy with cisplatln and 5-fluorouracfl for human gastric cancer xenograft lines of well-and poorly-differentiated adenocarcinomas transplanted in nude mice. Anticancer Res. (1992) 12:1295-1300.
219. KODA K, NAKAZAWA O, MORITA K et al: Combination chemotherapy of UFT with adriamycin (ADM) and cisplatin (CDDP) for advanced gastrointestinal cancer. Jpn.J. Cancer Chemother. (1990) 17:1893-1990.
220. HAYAKAWA M, MORISE K, SAKAI T et ah Combination chemotherapy with UFT, Etoposide, CDDP, Adriamycin (FEPA) in advanced gastric cancer. Jpn. J. Cancer Chemother. (1989) 16:3393-3398. (Pubitemid 19269890)
221. SAKUMAH, MATSUKIN. KATAYAMAK etal: EffectofPMU hepatic arterial chemotherapy for liver metastases of gastric cancer. Jpn.J. Cancer Chemother. (1989) 16:2557-2562.
222. KATO M, KINOSHITA K, SAWA T et al. Neoadjuvant chemotherapy for far advanced gastric cancer-effect of preoperative chemotherapy by PMUE (CDDP, MMC, UFT, Etoposide). Jpn.J. Cancer Chemother. (1990) 17:391-396. (Pubitemid 20167156)
223. SAWA T, KINOSHITA K. TAKEKAWA S et al. Effectof PMUE therapy (CDDP. MMC, UFT, Etoposide) for terminal gastric cancer. Jpn.J. Cancer Chemother. (1990) 17:2381-2386.
224. TATSUMIK, FUKUSHIMA M, SHIRASAKAT, FUJII S: Inhibitory effects of pyrimldlne, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn.J. Cancer Res. (Gann) (1987) 78:748-755. (Pubitemid 17132408)
225. SHIRASAKI T, SHIMAMOTO Y, FUKUSHIMA M: Inhibition by oxonlc acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res. (1993) 53:4004-4009. (Pubitemid 23267702)
226. CODACCI-PISANELLI G, VAN DER WILT CI, PINEDO HM et al: Antitumor activity, toxicity and inhibition of thymldylate synthase of prolonged administration of 5-fluorouracil In mice. Eur. J. Cancer (1995) 31A:1517-1525.
227. HORKOSHI N, MITACHI Y, SAKATA Y, SUGIMACHI K, TAGUCHI T: S-l, a new oral fluoropyrimidine Is very active in patients with advanced gastric cancer (early Phase n study). Proc. ASCO (1996) 15:206.
228. TAGUCHI T, HORKOSHI N, KINOSHITA H, TOGE T, TAKASHIMA S: Early Phase n study of s-l in patients with advanced breast cancer. Proc. ASCO (1996) 15:121.
229. KULIKOWSKI T: Structure-activity relationships and conformational features of antiherpetlc pyrimldlne and purine nucleoside analogues: a review. Pharmacy World Sci. (1994) 16:127-138. (Pubitemid 24142454)
230. DESGRANGES C, RAZAKA G, DE CLERCQ E et al: Effect of E-5-2- bromovinyluracil on the catabolism and antitumor activity of 5-fluorouracil in rats and leukemic mice. Cancer Res. (1986) 46:1094-1101. (Pubitemid 16048236)
231. KEIZER HJ, PAUWELS R, LANDUYT W et al Combined effects of bromovinyldeoxyridine and fractionated or continuous administration of 5-fluorouracil in P388 leukemia-bearing mice. Cancer Lett. (1988) 39:217-223.
232. IIGO M, ARAKI E, NAKAJIMA Y, HOSHI A, DE CLERCQ E: Enhancing effect of bromovinyldeoxyuridine on antitumor activity of 5-fluorouracil against adenomacard-noma 755 in mice. Increased therapeutic index and correlation with increased plasma 5-fluorouracil levels. Biochem. Pharmacol (1988) 37:1609-1613. (Pubitemid 18093357)
233. IIGO M, YAMAIZUMI Z, NISHIMURA S, HOSHI A, DE CLERCQ E: The antitumor potency of oraltegafur against adenocarcinoma 755 in mice is markedly enhanced by oral (e)-5-(bromovinyl)-2'-deoxyurldine. Jpn.J. Cancer Res. (Gann) (1987) 78:409-413. (Pubitemid 17102287)
234. KEIZER HJ, DE BRUIJN EA, TJADEN UR, DE CLERCQ: Inhibition of fluorouracil catabolism in cancer patients by the antiviral agent (E)-5-(2-bromovlnyl)-2'- de-oxyurkUne. J. Cancer Res. Clin. Oncol. (1994) 120:545-549 (Pubitemid 24246572)
235. PETERS GJ, SCHORNAGEL JH, MILANO GA: Clinical pharmacokinetics of antimetabolites. Cancer Surveys (1993) 17:123-156.
236. PORTER DJT, CHESTNUT WG, MERRILL BM, SPECTOR T: Mechanism-based inactlvation of dihydropyrimidine dehydrogenase by 5-ethynyluraciL. J. Biol. Chem. (1992) 267:5236-5242.
237. SPECTOR T, HARRINGTON JA, PORTER DJT: 5-Ethynyluracil (5-ethynyIuraclI): Inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem. Pharmacol. (1993) 46:2243-2248. (Pubitemid 24012317)
238. BACCANARI DP, DAVIS ST, KNICK VC, SPECTOR T. 5-Ethynyluracil: Effects on the pharmacokinetics and antitumor activity of 5-fluorouraciL Proc. Natl. Acad. Sci. (1993) 90:11064-11068. (Pubitemid 23354369)
239. CAO S, RUSTUM YM, SPECTOR T: 5-Ethynyluracil (776c85): modulation of 5-fluorouracil efficacy and therapeutic index In rats bearing advanced colorectal carcinoma. Cancer Res. (1994) 54:1507-1510. (Pubitemid 24106414)
240. SPECTORT, CAOS, RUSTUM YMJARRINGTONJA, PORTER DJT: Attenuation of the antitumor activity of 5-fluorouracU by (r)-5-fluoro-5,6-dihydrouraclL Cancer Res. (1995) 55:1239-1241.
241. CAO S, BACCANARI DP, JOYNER SS et al.: 5-Ethynyluracil (776c85): effects on the antitumor activity and pharmacokinetics of tegafur, a prodrug of 5-fluorouracil. Cancer Res. (1995) 55:6227-6230.
242. BAKER SD, DOUCETTE M, KHOR SP et al.: 776C85, an inactivator of dihydropyrimidine dehydrogenase (DPD), increases the plasma half-life, alters the disposition, and Increases the bioavailability of oral 5-fhiorouracil (5-FU). Proc. 9th NCI-EORTC Symp. Ann. Oncol. (1996) 7(Suppl. 1):68, [Abstract 2311.
243. BURRIS H, VON HOFF D, RATAIN M et al Initial Phase I trial of the dihydropyrimidine dehydrogenase Inactlva-tor 5-ethynyluracil (776C85) phis 5-fluorouracil (5-FU). Proc. 9th NCI-EORTC Symp. Ann. Oncol. (1996) 7(Suppl. 1):29, [Abstract 060].
244. KHOR SP, LUCAS S, SCHILSKY R et al: A Phase I/Pharma-coklnetlc Study of 5-Ethynyluracffl Phis 5-Fluorouracll in Cancer Patients with Solid Tumors. Proc. Am. Acad. Cancer Res. (1995) 36:241, [Abstract 14391]
245. TUCHMAN M, STOECKELER JS, KIANG DT el al. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. New Engl. J. Med. (1985) 313:245-249. (Pubitemid 15068641)
246. DIASIO RB, BEAVERS TL, CARPENTER JT: Familial deficiency In dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidlnenia and severe 5-fluorouracil-Induced toxicity. J. Clin, invest. (1988) 81:47-51. (Pubitemid 18092231)
247. HOUYAN P, GAY C, CHATELUT E et al:. Severe fluorouracil toxicity in a patient with decreased dihydropyrimidine dehydrogenase deficiency. J. Natl. Cancer Inst. (1993) 85:1602-1603. (Pubitemid 23304690)
248. GUO X, LERNERTUNG M, CHEN HX et al: 5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil. Biochem. Pharmacol. (1995) 49:1111-1116.
249. FUJII S, FUKUSHIMA M, SHIMAMOTO Y et al: Antitumor activity of bof-a2, a new 5-fluorouracil derivative. Jpn.J. Cancer Res. (1989) 80:173-181. (Pubitemid 20027672)
250. NAKAI Y, FURUSE K, OHTA M et al: Efficacy of a new 5-fluorouracil derivative, BOF-A2, In advanced non-small cell lung cancer-a multi-center Phase n study. Acta Oncologica (1994) 33:523-526. (Pubitemid 24292050)
251. OZAKI S: Synthesis and antitumor activity of 5-fluorouracil derivatives. Med. Res. Rev. (1996) 16:51-86. (Pubitemid 26037076)
252. BOLWELL BJ, CASSILETH PA, GALE RP: High dose cytarablne: a review. Leukemia (1988) 2:253-260.
253. PLUNKETT W, GANDHI V: Pharmacokinetics of arabino-sylcytoslne. J. Infusional Chemother. (1992) 2:169-176.
254. PLUNKETT W, GANDHI V: Cellular pharmacodynamics of anticancer drugs. Semin. Oncol. (1993) 20:50-63. (Pubitemid 23082218)
255. RODRIGUEZ G: Fludarabine phosphate. Invest. New Drugs (1994) 12:75-92.
256. PIRO LD, CARRERA CJ, CARSON DA, BEUTLER E: Lasting remissions in hairy-cell leukemia Induced by a single Infusion of 2-chIorodeoxy adenosine. New Engl. J. Med. (1990) 322:1117-1121. (Pubitemid 20149529)
257. KLOHS WD, KRAKER AJ: Pentostatin-future directions. Pharmacol. Rev. (1992) 44:459-477.
258. RUIZ VAN HAPEREN VWT, PETERS GJ: New targets for pyrimldlne antimetabolites for the treatment of sohd tumours. 2. Deoxycytidlne kinase. Pharm. World Sci. (1994) 16:104-112. (Pubitemid 24142452)
259. /,2'-difluorodeoxycytidine and 1-S-D-arabino-furanosylcytosine. Cancer Res. (1988) 48: 4024-031.
260. ERIKSSON S: Substrate specificities and expression of deoxynucleoside kinases; implications for cancer therapy. Proc. NCI-EORTC(1996) 9:27.
261. HUANG P, CHUBB S, HERTEL LW, GRINDEY GB, PLUNKETT W: Action of 2',2'-Difluorodeoxycytidlne on DNA Synthesis. Cancer Res. (1991) 51:6110-6117.
262. RUIZ VAN HAPEREN VWT, VEERMAN G, VERMORKEN JB, PETERS GJ: 2',2'-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA from tumour cell lines. Biochem. Pharmacol. (1993) 46:762-766. (Pubitemid 23262974)
263. RUIZ VAN HAPEREN VWT, BOVEN E et al: Schedule-dependence of sensitivity to 2/,2'-dlfluorodeoxycytidine (Gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumor cell lines and solid tumors. Biochem. Pharmacol. (1994) 48:1327-1339.
264. HUANG P, PLUNKETT W: A quantitative assay for fragmented DNA in apoptotic cells. Anal. Biochem. (1992) 207:163-167.
265. PLUNKETT W, HUANG P, XU YZ et al: Gemcitabine: metabolism, mechanisms of action, and self-potentla-tion. Semin. Oncol. (1995) 22(Suppl. 11):3-10.
266. RUIZ VAN HAPEREN VWT, VEERMAN G, SMID K, PINEDO HM, PETERS GJ: Gemcitabine inhibits thymidylate synthase (TS) activity in solid tumor cell lines. Proc. Am. Assoc. Cancer Res. (1995) 36: 354, [Abstract 2107].
267. BRAAKHUIS BJM, RUIZ VAN HAPEREN VWT, BOVEN E, VEERMAN G, PETERS GJ: Schedule dependent antitumor effect of gemcitabine in in vivo model systems. Semin. Oncol. (1995) 22(Suppl. ll):42-46.
268. HERTEL LW, BODER GB, KROIN JS etal.: Evaluation of the antitumor activity of a (2',2'-dlfluoro-2'-deoxycytidine). Cancer Res. (1990) 50:4417-4422.
269. BRAAKHUIS BJM, VAN DONGEN GMAS, VERMORKEN JB, SNOW GB: Preclinical in vivo activity of 2,2-dlfluorode-oxycytidlne (gemcitabine) agaist human head and neck cancer. Cancer Res. (1991) 51:211-214.
270. BOVEN E, SCHIPPER H, ERKELENS CAM, HATTY SA, PINEDO HM: The Influence of schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer. Br. J. Cancer (1993) 68:52-56. (Pubitemid 23178550)
271. VEERMAN G, RUIZ VAN HAPEREN VWT, VERMORKEN JB, PINEDO HM, PETERS GJ: Superior therapeutic activity of prolonged compared to bolus administration of 2',2'-dl-fluorodeoxycytidine (gemcitabine) in vivo against murine colon tumors. Cancer Chemother. Pharmacol. (1996). In press.
272. OROURKE TJ, BROWN TD, HAVLIN K etal.: Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days. Eur. J. Cancer. (1994) 30A:417-419.
273. POPLIN EA, CORBETT T, FLAHERTY L et al: Difluorode-oxycytidine (dFdC)-gemcitabine: a Phase I study. Invest. New Drugs (1992) 10:165-170.
274. Abbruzzese JL, Grunewald R, Weeks EA et al. A Phase I clinical, plasma and cellular pharmacology study of gemcitabine. J. Clin. Oncol (1991) 9:491-498.
275. ANDERSON H, THATCHER N, WALLING J, HANSEN H, MEJDAL P: A Phase I study of 24 hour Infusion of gemcitabine in patients 'with previously untreated, locally advanced, non-small cell lung cancer. Proc. ASCO (1994) 13:348, (Abstract 1164).
276. ABRATT RP, BEZWODA WR, FALKSON G: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a Phase H study. J. Clin. Oncol (1994) 12:1535-1540. (Pubitemid 24244986)
277. ANDERSON H, LUND B, BACH F et al: Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a Phase n study. J. Clin. Oncol. (1994) 12:1821-1826. (Pubitemid 24349383)
278. LUND B, HANSEN OP, THEILADE K, HANSEN M, NEIJT JP: Phase n study of gemcitabine (2',2'-difluorodeoxycvtid-Ine) in previously treated ovarian cancer patients. J. Natl. Cancer Inst. (1994) 86:1530-1533 (Pubitemid 24330217)
279. CASPER ES, GREEN MR, KELSEN DP et at: Phase XL trial of gemcitabine (2,2'-dlfhiorodeoxycytldlne) in patients ■with adenocarcinoma of the pancreas. Invest. New Drugs (1994) 12:29-34. (Pubitemid 24209062)
280. CARMICHAEL J, POSSINGER K, PHILLIP P et al. Advanced breast cancer: a Phase n trial with gemcitabine. J. Clin. Oncol. (1995) 13:2731-2736.
281. HANSEN HH: Gemcitabine-a review. Proc. 9th NCI-EORTC Symp. Ann. Oncol. (1996) 7(Suppl. 1):29, [Abstract 058].
282. CORMIER Y, EISENHAUER E, MULDAL A et al.: Gemcitabine Is an active new agent in previously untreated extensive small cell hing cancer (SCLC). Ann. Oncol. (1994) 5:283-285.
283. CHRISTMAN K, KELSEN D, SALTZ L: Phase II trial of gemcitabine in patients with advanced gastric cancer. Cancer (1994) 73: 5-7. (Pubitemid 24012713)
284. MOORE DF Jr, PAZDUR R, DAUGHERTY K, TARASSOFF P AND ABBRUZZESE JL: Phase n study of gemcitabine In advanced colorectal adenocarcinoma. Invest. New Drugs (1992) 10. 323-325. (Pubitemid 23008982)
285. CATIMEL G, VERMORKEN JB, CLAVEL M et al: A Phase H study of gemcitabine (LY 188011) In patients with advanced squamous cell carcinoma of the head and neck. Ann. Oncol. (1994) 5:543-547. (Pubitemid 24223508)
286. GRUNEWALD R, KANTARJIAN H, DU M et al: Gemcitabine in leukemia: a Phase I clinical, plasma and cellular pharmacology study. J. Clin. Oncol. (1992) 10:406-413.
287. PETERS GJ, BERGMAN AM, VAN HAPEREN VWTR et al: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin. Oncol. (1995) 22(Suppl. ll):72-79.
288. BERGMAN AM, RUIZ VAN HAPEREN VWT, VEERMAN G et al: Synergistic interaction between gemcitabine and clsplatln in vitro. Clin. Cancer Res. (1996) 2:521-530. (Pubitemid 26099172)
289. VAN MOORSEL CJA, VEERMAN G, KUIPER C et al: Synergism between gemcitabine and clsplatln in ovarian and non-small cell lung cancer cell lines. Proc. 9thNCI-EORTC Ann. Oncol. (1996) 7(Suppl. 1):65, [Abstract 2191]
290. BRAAKHUIS BJM, RUIZ VAN HAPEREN VWT, WELTERS MJP, PETERS GJ: Schedule-dependent therapeutic efficacy of the combination of gemcitabine and clsplatln in head and neck cancer xenografts. Eur. J. Cancer (1995) 31A:2335-2340. (Pubitemid 26050580)
291. CRINO L, SCAGLIOTTI G, MARANGOLO M et al: Cisplatin gemcltablne combination in non-small cell lung cancer (NSCLC). A Phase U study. Proc. ASCO (1995) 14:352, [Abstract 1066].
292. SANDLER AB, ANSARI R, MCCLEAN J et al: A Hoosier Oncology Group Phase n study of gemcitabine plus cisplatin in non-small cell lung cancer (NSCLC). Proc. ASCO (1995) 14:357, [Abstract 10891.
293. ABRATT RP, BEZWODA WR, GOEDHALS L, HACKING DJ: Gemcitabine and cisplatin for advanced non-small cell hing cancer (NSCLC). Proc. ASCO (1996) 15:380, [Abstract 1136].
294. STEWARD WP, DUNLOP DJ, CAMERON C et al: Phase I/O study of cisplatin in combination with gemcitabine in non-small cell lung cancer (NSCLC). Proc. ASCO (1995) 14:351, (Abstract 1064).
295. SHEPHERD F, CORMIER Y, EVANS W etal: A Phase H study of gemcitabine and cisplatin weekly x 3 every 4 weeks in patients with non-small cell lung cancer (NSCLC). Proc. ASCO (19%) 15:380, [Abstract 1135]
296. ANTON A, CARRATO A, GONZALES LARRIBA JL et al: Phase n activity of gemcitabine in combination with cisplatin in advanced non-small cell lung cancer (NSCLC). Proc. ASCO (1996) 15:380, [Abstract 1134].
297. ROTHENBERG ML, ECKARDT JR, STEPHENS S et al. A Phase I trial of gemcitabine and paclrtaxel administered on an every other week schedule. Proc. 9th NCI-EORTC meeting [Abstract 319]. Ann. Oncol. (1996) 7(Suppl. D.)925.
298. MANEGOLD CH, EBERHARD W, WILKE H et al: Phase n study of gemcitabine (GEM) and ifosfamide (BFO) in advanced non-small cell lung cancer (NSCLC). Proc. ASCO (1996) 15:380, [Abstract 1137].
299. PEREZ-MANGA G, LLUCH A, GARCIA-CONDE J etal: Early Phase n study of gemcitabine in combination with doxorubicin in advanced breast cancer. Proc. ASCO (1995) 14:97, [Abstract 89].
300. PLUNKETT W, GANDHI V: Evolution of the arabinosides and the pharmacology of fhidarablne. Drugs (1994) 47(Suppl. 6):30-38.
301. CATAPANO CV, CHANDLER KB, FERNANDES DJ: Inhibition of primer RNA formation In CCRF-CEM leukemia cells by fhidarablne triphosphate. Cancer Res. (1991) 51:1829-1835.
302. YANG S-W, HUANG P, PLUNKETT W, BECKER FF, CHAN JYH: Dual mode of inhibition of purified DNA Ugase I from human cells by 9-fi-D-arablnofuranosyl- 2-fluoroadenine triphosphate. J. Biol. Chem. (1992) 267:2345-2349.
303. ROBERTSON LE, CHUBB S, MEYN RE et al: Induction of Apoptotic Cell Death In Chronic Lymphocytic Leukemia by 2-Chloro-2'-Deoxyadenosine and 9-beta-D-Arabino-syl-2-Fhioroadenlne. Stoorf(1993) 81:143-150. (Pubitemid 23013688)
304. DOW LW, BELL DE, POULAKOS L, FRTDLAND A: Differences in metabolism and cytotoxicity between 9-&-arabinofuranosyladenine and 9-6-arabino-furanosyl- 2-fluoroadenine in human leukemic h/mphoblasts. Cancer Res. (1980) 40:1405-1410. (Pubitemid 10101976)
305. KEATING MJ, ESTEY E, O'BRIEN S et al: Clinical experience with fhidarablne in leukaemia. Drugs (1994) 47(Suppl. 6):39-49.
306. KEATING MJ, KANTARJIAN H, O'BRIEN S et al: Fludarabine: A new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J. Clin. Oncol. (1991) 9.44-49.
307. KEATING MJ, MCLAUGHLIN P, PLUNKETT W et al: Fludarabine-present status and future developments in chronic lymphocytic leukemia and lymphoma. Ann. Oncol. (1994) 5(Suppl. 2):S79-S83.
308. AVRAMISVI, CHAMPAGNE J, SATO J et al:. Pharmacology of fludarabine phosphate after a Phase I/H trial by a loading bolus and continuous Infusion In pediatric patients. Cancer Res. (1990) 50:7226-7231.
309. MITTELMAN A, LICHTMAN S, BUDMAN D et al: Therapy of chronic lymphocytic leukemia (CLL) with fludarabine phosphate (FAMP). Blood (1988) 72250a
310. PUCCIO CA, MITTELMAN A, LICHTMAN SM etal: A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia. J. Clin. Oncol. (1991) 9:1562-1569.
311. HIDDEMANN W, ROTTMANN R, VORMANN B et al: Treatment of advanced chronic lymphocytic leukemia by fludarabine: results of a clinical Phase n study. Ann. Hematol. (1991) 63:1-4.
312. KANTARJIAN HM, CHILDS C, O'BRIEN S et al:. Efficacy of fludarabine, a new adenine nucleoside analogue, in patients with prolymphocytic leukemia and the pro-rymphocytoid variant of chronic lymphocytic leukemia. Am. J. Med. (1991) 90.223-228.
313. GREVER MR, COLTMAN CA Jr, FILES JC et al: Fludarabine therapy in hairy cell leukemia. Cancer (1986) 67:1291-1293.
314. GANDHI V, KEMENA A, KEATING MJ et al: Fludarabine Infusion potentiates arabinosylcytosine in lymphocytes in patients with chronic lymphocytic leukemia. Cancer Res. (1992) 52:897-903.
315. GANDHI V, ESTEY E, KEATING MJ et al: Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J. Clin. Oncol. (1993) 11:116-124. (Pubitemid 23059984)
316. GREGOIRE V, VAN NT, STEPHENS C et al: The role of fludarablne-induced apoptosis and cell cycle synchronization in enhanced murine tumor radiation response in vivo. Cancer Res. (1994) 54:6201-6209. (Pubitemid 24378654)
317. KEFFORD RF, FOX RM: Purinogeniclymphocytotoxicity: clues to a 'wider chemotherapeutlc potential for the adenosine deaminase inhibitors. Cancer Chemother. Pharmacol. (1983) 10:73-78. (Pubitemid 13110775)
318. CARSON DA, KAYE J, MATSUMOTO S, SEEGMILLER JE, THOMPSON LF: Biochemical basis for the enhanced toxicity of deoxyribonucleosides toward malignant human T cells. Proc.Natl. Acad. Sci. USAH(1979) 76:2430-2433.
319. CARSON DA, WASSON DB, KAYE J et al.: Deoxycytldine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine LI210 leukemia in vivo. Proc. Natl. Acad. Sci. (1980) 77:6865-6869. (Pubitemid 11219046)
320. PLUNKETT W, SAUNDERS PP: Metabolism and action of purine nucleoside analogs. Pharmacol. Ther. (1991) 49:239-268.
321. CHUNDURU SK, APPLEMAN JR, BLAKLEY RL: Activity of human DNA-polymerases a and (J with 2-chloro-2'-de-oxydenosine 5-triphosphate as a substrate and quantitative effects of incorporation on chain extension. Arch. Biochem. Biophys. (1993) 302:19-30. (Pubitemid 23212610)
322. CARSON DA, WASSON DB, ESPARZA LM et al: Oral An-thymphocyte Activity and Induction of Apoptosis by 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine. Proc. Natl. Acad. Sci. USA (1992) 89:2970-2974.
323. PIRO LD, CARRERA CJ, BEUTLER E, CARSON DA: 2-Chlo-rodeoxyadenosine: an effective new agent for die treat-ment of chronic lymphocytic leukemia. Blood (1988) 72:1069-1073
324. PIRO LD, CARRERA CJ, CARSON DA, BEUTLER E: Lasting remissions in hairy-cell leukemia Induced by a single infusion of 2-chlorodeoxyadenosine. New Engl. J. Med. (1990)322:1117-1121. (Pubitemid 20149529)
325. CHESON BD, VENA DA, FOSS FM, SORENSEN JM: Neurotoxicity of purine analogs: a review. J. Clin. Oncol. (1994) 12:2216-2228. (Pubitemid 24356042)
326. SANTANA VM, MIRRO J, KEARNS C et al: 2-Chlorode-oxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J. Clin. Oncol. (1992) 10:364-370.
327. JULIUSSON G, ELMHORNROSENBORG A, LILIEMARK J: Response to 2-chlorodeoxyadenosine in patients with b-cell chronic lymphocytic leukemia resistant to fludarabine. New Engl. J. Med. (1992) 327:1056-1061.
328. O'BRIEN S, KURZROCK R, DUVIC M et al: 2-Chlorode oxyadenosine therapy in patients with t-cell h/mpho-prollferative disorders. Blood (1994) 84:733-738. (Pubitemid 24223867)
329. SANTANA VM, HURWITZ CA, BLAKLEY RL et al: Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia. Blood (1994) 84:1237-1242. (Pubitemid 24245891)
330. KRISTENSENJ, NYGREN P, LEJEMARKJ etal: Interactions between cladrlbine (2-chlorodeoxyadenosine) and standard antileukemic drugs in primary cultures of human tumor cells from patients with acute myelocytic leukemia. Leukemia (1994) 8:1712-1717.
331. TEFFERI A, WITZIG TE, REID JM, LI C-Y, AMES MM: Phase I study of combined 2-chlorodeoxyadenosine and chlorambucS In chronic lymphoid leukemia and low-grade lymphoma. J. Clin. Oncol. (1994) 12:569-574. (Pubitemid 24079900)
332. CORY JG: Role of ribonucleotide reductase in cell division. In: Inhibitors of Ribonucleoside Diphosphate Reductase Activity, International Encyclopedia of Pharmacology and Therapeutics. Cory JG, Cory AH (Eds.), Pergamon Press, New York (1989) Section 128:1-16.
333. BITONTIAJ, BUSH TL, LEWIS MT, SUNKARA PS: Response of human colon and prostate tumor xenografts to (£)-2'-deoxy-2'-(fluoromethylene) cytidine, an inhibitor of ribonucleotide reductase. Anticancer Res. (1995) 15:1179-1182.
334. BITONTI AJ, DUMONT JA, BUSH TL: Regression of hu-masn breast tumor xenografts In response to (c)2'-de-oxy-2"-(fluoromethylene)cytidine, an inhibitor of ribonucleoside diphosphate reductase. Cancer Res. (1994) 54:1485-1490.
335. CORYJG, CORY AH, RAPPA G etal: Inhibitors of ribonu cleotide reductase: comparative effects of amino-and hydroxy-substituted pyridine-2-carboxaldehyde thiosemlcarbazones. Biochem. Pharmacol. (1994) 48:335-344.
336. CARMICHAEL J, CANTWELL BMJ, MANNLX KA: A Phase I and pharmacokinetic study of didox: a ribonucleotide reductase inhibitor. Br. J. Cancer (1990) 61:447450.
337. RUBENS RD, KAYE SB, SOUKOP M et al: Phase H trial of didox in advanced breast cancer. Br. J. Cancer (1991) 64:1187-1188.
338. SZEKERES T, GHAREHBAGHI K, FRITZER M et al: Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase. Cancer Chemother. Pharmacol. (1994) 34:63-66. (Pubitemid 24194560)
339. HUBER BE, AUSTIN EA, RICHARDS CA, DAVIS ST, GOOD SS: Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cy-tosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc. Natl. Acad. Set. USA (1994) 91:8302-8306.
340. JIA WWG, MCDERMOTT M, GOLDIE J et at.: Selective destruction of gliomas in immunocompetent rats by thymidine kinase-defective herpes simplex virus type 1. J. Natl. Cancer Inst. (1994) 86:1209-1215. (Pubitemid 24253695)
341. RAM Z, WALBRIDGE S, SHAWKER T et al: The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. J. Neurosurgery (1994) 81:256-260. (Pubitemid 24238006)
342. TAPSCOTT SJ, MILLER AD, OLSON JM etal: Gene therapy of rat 9L gllosarcoma tumors by transduction with selectable genes does not require drug selection. Proc. Natl. Acad. Set. USA (1994) 91:8185-8189. (Pubitemid 24253911)
343. WU JK, CANO WG, MEYLAERTS SAG et al: Bystander tumoricldal effect in the treatment of experimental brain tumors. Neurosurgery (1994) 35.1094-1102.
344. RAFFELC, CULVER K, KOHN D etal: Gene therapy for the treatment of recurrent pediatric malignant astrocytomas with in vivo tumor transduction 'with the herpes simplex thymidine kinase gene/ganciclovlr system. Human Gene Therapy (1994) 5:863-890. (Pubitemid 24310573)
345. TJUVAJEV JG, STOCKHAMMER G, DESAI R et al: Imaging the expression of transfected genes in vivo. Cancer Res. (1995) 55:6126-6132.
346. BANERJEE D, ZHAO SC, LI M-X et al: Gene therapy utilizing drug resistance genes: a review. Stem Cells (1994) 12:378-385. (Pubitemid 24243720)
347. SORM F, VESELY J: Effect of 5-aza-2'-deoxycytidine against leukaemlc and haemopoietic tissues in AKR mice. Neoplasma (1968) 15:339-343.
348. GOVER AB, LEYLAND-JONES BR, CHUN HG, DAVIES B, HOTH DF: Azacytidlne: 10 years later. Cancer Treat. Rep. (1987) 71:737-746.
349. GLOVER AB, LEYLAND-JONES B: Biochemistry of azacytidlne: a review. Cancer Treat. Rep. (1987) 71:959-964.
350. MOMPARLER RL, GONZALEZ FA: Effect of intravenous infusion of 5-aza-2'-deoxycytidine on survival induction of mice with L1210 leukemia Cancer Res. (1978) 38:2673-2678. (Pubitemid 9001505)
351. RICHEL DJ, COLLY LP, LURVINK E, WILLEMZE R: Comparison of the antileukaemic activity of 5-aza-2-deoxycytid-Ine and arabinofuranosylcytosine In rats with myelocytic leukaemia Br. J. Cancer (1988) 58:730-733. (Pubitemid 19033385)
352. RICHEL DJ, COLLY LP, LURVINK E, WILLEMZE R: Activity of 5-aza-2-deoxycytidine in Ara-c-resis tant and sensitive leukemia. Contrib. Oncology (1989) 37:20-29.
353. RICHEL DJ, COLLY LP, KLUIN-NELEMANS JC, WILLEMZE R: The antileukaemic activity of 5-aza-2'-deoxycytidlne In patients with relapsed and resistant leukaemia. Br. J. Cancer(1988) 64:144-148.
354. BRAAKHUIS BJM, VAN DONGEN GAMS, VAN WALSUM M, LEYVA A, SNOW GB: Preclinical antitumour activity of 5-aza-2'-deoxycytidine against human head and neck cancer xenografts. Invest. New Drugs (1988) 6:299-304. (Pubitemid 19010328)
355. STEGMANN APA, HONDERS MW, KESTER MGD, LANDE-GENT JE, WILLEMZE R: Role of deoxycytidine kinase in an in vitro model for ara-C and DAC resistance: substrate-enzyme interactions with deoxycytidine, 1-p-Darabinofuranosylcytoslne and 5-aza-2'-deoxy cytidine. Leukemia (1993) 7:1005-1011. (Pubitemid 23230980)
356. RUIZ VAN HAPEREN VWT, VEERMAN G, ERIKSSON S et al: Development and characterisation of a 2',2'-difiuorode-oxycytidine-resistant variant of the human ovarian cancer cell line A2780. Cancer Res. (1994) 54:4138-4143.
357. TAYLOR SM: 5-Aza-2'-deoxycycytidlne-cell differentiation and DNA methylation. Leukemia (1993) 7(Suppl. l):3-8.
358. JUTTERMAN R, LI E, HAENISCH R: Toxicity of 5-aza-2'-de-oxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA dememylation. Proc. Nat. Acad. Set. USA (1994) 91:11797-11801.
359. ATTADIA V, SAGLIO G, FUSCO A, DiFIORE PP, PINTO A: Effects of 5-aza-2'-deoxycyctldlne on erythroid differentiation and globln synthesis of the human leukaemlc cell line K562. In. 5-Aza-2'-Deoxycytidine. Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):89-103
360. SCHWARTSMANN G, PINEDO HM, LEYVA A: Resistance of HL60 promyelocytic leukaemia cells to Induction of differentiation and its reversal by combination treatment Eur. J. Cancer Clin. Oncol. (1987) 23:739-743. (Pubitemid 17119711)
361. ATTADIA V: Effects of 5-aza-2'-deoxycytidine on differentiation and oncogene expression in the human monoblastic leukemia cell line U-937. Leukemia (1993) 7(Suppl. 1):9-16. (Pubitemid 23184794)
362. CARPINEIXI P, GRANATA F, AUGUSTITOCCO G, ROSSI M, BARTOLUCCI S: Antiproliferative effects and DNA hy-pomethylation by 5-aza-2'-deoxycytldine in human neuroblastoma cell lines. Anti-Cancer Drugs (1993) 4:629-635. (Pubitemid 24026215)
363. BARTOLUCCI S, CARPINEIXI P, ROSSI M, MIMPARLER RL: Inhibition of proliferation and DNA methylation in human neuroblastoma cells by 5-aza-2'-deoxycytidlne. In: 5-Aza-2'-Deoxycytidine: Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):35-42.
364. SAGER R, KOVAC P: Preadipocyte determination either by insulin or azacytidlne. Proc. Natl. Acad. Sci. USA (1982) 79:480-84. (Pubitemid 12137734)
365. WEBER J, SALGALLERM, SAMID D el al.: Expression of the MAGE-1 tumour antigen is up-regulated by the de-methylating agent 5-aza-2'-deoxycytldlne. Cancer Res. (1994) 54:1766-1771.
366. CHABOT CG, MOMPARLER RL: Effect of 5-aza-2'-deoxy-cytidine on survival and cell cycle progression of 1.1210 leukaemia cells. Leukem. Res. (1986) 10:533-537. (Pubitemid 16118157)
367. LEYVA A, BOEIJE LCM, DE WAAL F, PINEDO HM: Antitumour effects of 5-aza-2'-deoxycytidine In aquamous cell carcinoma lines in vitro. In: 5-Aza-2-Deoxycytidine: Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):49-58.
368. PINTO A, ZAGONEL V: 5-Aza-2'-deoxycytidlne (ded-tabine) and 5-azacytldlne in the treatment of acute myeloid leukemlas and myelodysplastic syndromes-past, present and future trends. Leukemia (1993) 7(Suppl. l):51-60. (Pubitemid 23184801)
369. PINTO A, ZASGONEL V, GATTEI V et al: 5-Aza-2'-deoxy-cytldine as a differentiation inducer in human hemopoietic malignancies: preliminary observations on the in vivo modulation of leukemia cell phenotype and correlations ■with clinical response. In: 5-Aza-2-De-oxycytidine: Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):143-164.
370. MOMPARLER RL, GYGER M, RTVARD GE: Clinical trial on 5-aza-2- 'deoxycytidine in patients with acute leukemia. Pharmacol. Ther. (1985) 30:277-286. (Pubitemid 17207209)
371. DU BUSCHER L, MARIE JP, DODION P, BLANC GM, ARRIGO C, ZITOUN R, STRYCKMANS P: Phase in trials of 5-aza-2'-deoxycytidine in adult patients with acute leukemia. In: 5-Aza-2-Deoxycytidine Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):131-142.
372. WILLEMZE R, ARCHIMBAUD E, MUUS P FOR THE EORTC LEUKAEMIA COOPERATIVE GROUP: Preliminary results of 5-aza-2'-deoxycytidine-containing chemotherapy in patients with relapsed or refractory acute leukaemia. Leukaemia (1993) 7(Suppl. l):49-50. (Pubitemid 23184800)
373. PETTI MC, MANDELLI F, ZAGQNEL V et al: Pilot study of 5-aza-2'-deoxycytldine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients-preliminary results. Leukemia (1993) 7(Suppl. 1):36-41. (Pubitemid 23184798)
374. VAN GROENINGEN CJ, LEYVA A, O'BRIEN AMP, GALL HE, PINEDO HM: Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) In cancer patients. Cancer Res. (1986)46:4831-4836. (Pubitemid 16000370)
375. CHABOT CG, MOMPARLER RL: Pharmacokinetics of 5-aza-2'-deoxycytidine in animals and man: relevance to clinical trials. In: 5-Aza-2-Deoxycytidine: Preclinical and Clinical Studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):105-H5.
376. DODION PF, CLAVEL M, TENBOKKELHUININK W et al: Phase n trials with 5-aza-2'-deoxycyidine by the Early Clinical Trials Group for the EORTC. In: 5-Aza-2-Deoxycytidine: Preclinical and Clinical Studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):117-124.
377. WAGNER DJT,DE MULDER PHM, CLAVEL M: Preliminary results of a Phase I trial of 5-aza-2'-deoxycytldine daily times 5 four hour infusions. In: 5-Aza-2'-Deoxycytidine: Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):125-130.
378. ZAGONEL V, LORE G, MAROTTA G et al: 5-Aza-2'-deoxy-cytldine (decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Leukemia (1993) 7(Suppl. l):30-35. (Pubitemid 23184797)
379. WIJERMANS PW: Continuous infusion of low-dose deci tabine in high-risk MDS patients. Workshop on the Clinical Results with Decitabine (5-aza-2-deoxycytidine) in Hema-tologic Malignancies. Pharmachemie BV, Haarlem, The Netherlands (1996):7, data on file.
380. KANTARIAN HM, O'BRIEN SM, ESTEY E et al: Decitabine studies In chronic and acute myelogenous leukemia. Workshop on the Clinical Results with Decitabine (5-aza-2-deoxycytidine) in Hematologic Malignancies. Pharmachemie BV, Haarlem, The Netherlands (1996):15-19, data on file.
381. ROSSI M, BARTOLUCCI S, MOMPARLER LF, MONMPARLER RL: Biochemical modulation of the antileukemic activity of 5-aza-2'-deoxycytidine by thymine. In: 5-Aza-2-Deoxycytidine: Preclinical and Clinical studies. Momparler RD, de Vos D (Eds.), PCH, Haarlem, The Netherlands (1990):43-48.
382. MOMPARLER RL, DORE BT, LABIBERTE J, MOMPARLER LF: Interaction of 5-aza-2'-deoxycytidine with amsacrine or l,25-dihydroxyvitamin-D(3) on HL-60 myeloid leukemic cells and inhibitors of cytidine deaminase. Leukemia (1993) 7(Suppl. l):17-20. (Pubitemid 23184795)
383. BOUFFARD DY, MOMPARLER LF, MOMPARLER, RL: Enhancement of the antileukemic activity of 5-aza-2'-de-oxycytidine by cyclopentenyl cytosine on HL-60 leukemic cells. Anti-Cancer Drugs (1994) 5:223-228. (Pubitemid 24161705)
384. ELLERHORST JA, FROST P, ABBRUZZESE JL, NEWMAN RA, CHERNAJOVSKY Y: 2'-Deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation. Br. J. Cancer (1993) 67:209-215. (Pubitemid 23049538)
385. WILLEMZE R, SUCIU S, ARCHIMBAUD E et al: A randomized Phase n study on the effects of 5-aza-2'-deoxycytid-ine combined with either amsacrine or idarubicin in patients with relapsed leukemia. Workshop on the Clinical Results with Decitabine (5-aza-2-deoxycytidine) in Hematologic Malignancies. Pharmachemie MS, Haarlem, The Netherlands (1996):10-11, data on file.
386. FERNANDES MS, SCHANN MD, MOSCKEN M et al: Daunomycin plus 5-aza-2'-deoxycytkUne as an induction regimen in patients 'with acute myeloid leukemia: preliminary results. Workshop on the Clinical Results with Decitabine (5-aza-2-deoxycytidine) in Hematologic Malignancies. Pharmachemie MS, Haarlem, The Netherlands (1996):12, data on file.
387. GIRALTS, DAVIS M, O'BRIEN S etal: Studies of decitabine with allogenic progenitor cell transplantation. Workshop on the clinical results with decitabine (5-aza-2-deoxycytidine) in hematologic malignancies. Pharmachemie MS, Haarlem, The Netherlands (1996):13-14, data on file.
388. LENZI R, RABER MN, GRAVEL D, FROST P, ABBRUZZESE JL: Phase I and n trials of a laboratory-derived synergistic combination of cisplatin and 2'deoxy-5-azacytidine-clinical study. Int. J. Oncol. (1995) 6:447-450.