Tomudex™ (ZD1694): From concept to care, a programme in rational drug discovery

Investigational New Drugs

Volumn 14, Issue 3, 1996, Pages 305-316

  Jackman, Ann L ^a   Boyle, F Thomas ^b   Harrap, Kenneth R ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

Author keywords

Folylpolyglutamate synthetase; Thymidylate synthase; Tomudex

Indexed keywords

10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; ANTINEOPLASTIC AGENT; DIHYDROFOLATE REDUCTASE; FOLIC ACID; FOLIC ACID ANTAGONIST; FOLYLPOLYGLUTAMATE SYNTHASE; RALTITREXED; THYMIDYLATE SYNTHASE; ANTINEOPLASTIC ANTIMETABOLITE; ENZYME INHIBITOR; NEW DRUG; QUINAZOLINE DERIVATIVE; THIOPHENE DERIVATIVE;

COLORECTAL CANCER; DRUG SOLUBILITY; ENZYME INHIBITION; NEPHROTOXICITY; PRIORITY JOURNAL; REVIEW; ANIMAL; CHEMISTRY; COLORECTAL TUMOR; DRUG ANTAGONISM; DRUG DESIGN; HUMAN;

ANIMALS; ANTIMETABOLITES, ANTINEOPLASTIC; COLORECTAL NEOPLASMS; DRUG DESIGN; DRUGS, INVESTIGATIONAL; ENZYME INHIBITORS; FOLIC ACID ANTAGONISTS; HUMANS; QUINAZOLINES; THIOPHENES; THYMIDYLATE SYNTHASE;

EID: 0029658045     PISSN: 01676997     EISSN: None     Source Type: Journal    
DOI: 10.1007/BF00194534     Document Type: Article

References (83)

1. Bertino JR: Ode to methotrexate. J Clin Oncol 11:5-14, 1993
2. Myers CD: The pharmacology of the fluoropyrimidines. Pharm Revs 33:1-15, 1981
3. Peters GJ: Antimetabolites. In: Peckham M, Pinedo H (eds) The Scientific Basis for Cancer Treatment. Oxford University Press, Oxford, 1995, pp 524-552
4. Borsa J, Whitmore GF: Cell killing studies on the mode of action of methotrexate on L cells in vitro. Cancer Res 29:737-744, 1969
5. Rueckert RR, Mueller GC: Studies on unbalanced growth in tissue culture. I. Induction and consequences of thymidine deficiency. Cancer Res 20:1584-1591, 1960
6. Cohen SS, Studzinski GP: Correlation between cell enlargement and nucleic acid and protein content of HeLa cells in unbalanced growth produced by inhibitors of DNA synthesis. J Cell Physiol 69:331-340, 1968
7. Taylor W, Slowiaczek P, Francis PR, Tattersal MHN: Biochemical and cell cycle perturbations in methotrexate-treated cells. Mol Pharmacol 21:204-210, 1982
8. Fairchild CR, Maybaum J, Straw JA: Enhanced cytotoxicity with methotrexate in conjunction with hypoxantrine in L1210 cells in culture. Cancer Chemother Pharmacol 22:26-32, 1988
9. Smith SG, Lehman NL, Moran RG: Cytotoxicity of antifolate inhibitors of thymidylate and purine synthesis in WiDr colonic carcinoma cells. Cancer Res 53:5697-5706, 1993
10. Jackson RC, Niethammer D: Acquired methotrexate resistance in lymphoblasts resulting from altered kinetic properties of dihydrofolate reductase. Eur J Cancer 13:567, 1977
11. Harrap KR, Taylor GA, Browman GP: Enhancement of the therapeutic effectiveness of methotrexate and protection of normal proliferating tissues with purines and pyrimidines. Chem Biol Interactions 18:119-128, 1977
12. Ardalan B, Cooney D, Macdonald JS: Physiological and pharmacological determinants of sensitivity and resistance to 5-fluorouracil in lower animals and man. Adv Pharmacol Chem 17:289-321, 1990
13. Reichard P, Skold O, Klein G, Revesz I, Magnussom P-H: Studies on resistance against 5-fluorouracil. Cancer Res 22:235-243, 1962
14. Kasbekar DK, Greenberg DM: Studies on tumour resistance to 5-fluorouracil. Cancer Res 23:818-824, 1963
15. Ensminger WD, Rosowsky A, Raso V, Levin DC, Glode M, Come S, Steele G, Frei E III: A clinical pharmacological evaluation of hepatic arterial infusions of 5-fluoro-2′-deoxyuridine and 5-fluorouracil. Cancer Res 38:3784-3792, 1979
16. Myers CE, Young RC, Chabner BA: Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion. J Clin Invest 56:1231-1238, 1975
17. Klubes P, Connelly K, Cerna I, Mandel HG: Effects of 5-fluorouracil on 5-fluorodeoxyuridine 5′-monophosphate and 2-deoxyuridine 5′-monophosphate pools, and DNA synthesis in solid mouse L1210 and rat Walker 256 tumours. Cancer Res 38:2325-2331, 1978
18. Maybaum J, Cohen MB, Sadee W: In vivo rates of pyrimidine nucleotide metabolism in intact mouse T-lymphoma (S-49) cells treated with 5-fluorouracil. J Biol Chem 256:2126-2130, 1981
19. Jackson RC: The regulation of thymidylate biosynthesis in Novikoff hepatoma cells and the effects of amethopterin, 5-fluorodeoxyruridine, and 3-deazauridine. J Biol Chem 253:7440-7446, 1978
20. Lockshin A, Danenberg PV: Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol 30:247-257, 1981
21. Ullman B, Lee M, Martin Jr DW, Santi DV: Cytotoxicity of 5-fluoro-2′- deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 75:980-983, 1978
22. Houghton JA, Maroda SJ, Phillips JO, Houghton PJ: Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice. Cancer Res 41:144-149, 1981
23. Kohne-Womper C-H, Schmoll H-J, Harstrich A, Rustum YM: Chemotherapeutic strategies in metastatic colorectal cancer: An overview of current clinical trials. Semin Oncol 19(suppl 3):105-124, 1992
24. Sotos GA, Grogan L, Allegra CJ: Preclinical and clinical aspects of biomodulation of 5-fluorouracil. Cancer Treat Rev 20:11-49, 1994
25. Jones TR, Calvert AH, Jackman AL, Brown SJ, Jones M, Harrap KR: A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in mice. Eur J Cancer 17:11-19, 1981
26. Bird OD, Vaitkus JW, Clarke J: 2-amino-4-hydroxyquinazolines as inhibitors of thymidylate synthetase. Mol Pharmacol 6:573-575, 1970
27. Jackman AL, Jones TR, Calvert AH: Thymidylate synthetase inhibitors: Experimental and clinical aspects. In: Muggia FM (ed) Experimental and Clinical Progress in Cancer Chemotherapy. Martinus Nijhoff, Boston, 1985, pp 155-210
28. Jackson RC, Jackman AL, Calvert AH: Biochemical effects of a quinazoline inhibitor of thymidylate-synthetase, CB3717, on human lymphoblastoid cells. Biochem Pharmacol 32:3783-3790, 1983
29. Diddens H, Niethammer D, Jackson RC: Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Cancer Res 43:5286-5292, 1983
30. 10-propargyl-5,8-dideazfolate and its polyglutamates against human dihydrofolate reductase, human thymidylate synthase and KB cells containing different levels of dihydrofolate reductase. Cancer Res 45:598-600, 1985
31. Orr RM, Peacock J, Payne AWR, Goddard PM, Harrap KR: In vitro sensitivities of diploid and tetraploid L1210 cell lines to antineoplastic agents. In: Daikos GK, Giamarellou H (eds). Il Sedicesimo, Florence. Chemioterapia 4:1178-1179, 1985
32. Jackman AL, Calvert AH, Taylor GA, Harrap KR: Biological properties of the new quinazoline inhibitor of thymidylate synthetase CB3717. In: Davis W, Maltoni C, Tanneberger St (eds) The Control of Tumour Growth and Its Biological Bases. Academie Verlag, Berlin, 1983, pp 404-410
33. Curtin N, Harris AL, James OFW, Bassendine MF: Inhibition of the growth of hepatocellular carcinoma in vitro and in athymic mice by a quinazoline inhibitor of thymidylate synthase, CB3717. Brit J Cancer 53:361-368, 1986
34. Jackman AL: Folate-based inhibitors of thymidylate synthase as potential anticancer agents. Ph.D. Thesis, University of London, 1986
35. Jackman AL, Taylor GA, Calvert AH, Harrap KR: Modulation of antimetabolite effects: Effects of thymidine on the efficacy of the quinazoline-based thymidylate synthetase inhibitors, CB3717. Biochem Pharmacol 33:3269-3275, 1984
36. Stephens TC, Smith MN, Waterman SE, McCloskey ML, Jackman AL, Boyle FT: Use of murine L5178Y lymphoma thymidine kinase mutants for in vitro and in vivo antitumour efficacy evaluation of novel thymidine synthase inhibitors. In: Ayling JE, Nair MG, Baugh CM (eds) Chemistry and Biology of Pteridines and Folates. Advances in Experimental Medicine and Biology. Plenum Press, New York, 1993, Vol. 338, pp 589-592
37. Jackman AL, Calvert AH: Folate-based thymidylate synthase inhibitors as anticancer drugs. Annals of Oncology 6:871-881, 1995
38. Clarke SJ, Jackman AL, Judson IR: The history of the development and clinical use of CB3717 and ICI D1694. In: Rustum Y (ed) Proceedings of the International Symposium on Novel Approaches to Selective Treatments of Human Solid Tumours: Laboratory and Clinical Correlation. Adv Exptl Med Biol. Plenum Press, New York, 1993, Vol 339, pp 277-287
39. 10-propargyl-5,8-dideazfolid acid (CB3717) in the mouse. Cancer Treat Reps 70:871-979, 1986
40. 10-propargyl-5,8-dideazafolic acid (CB3717). Cancer Chemother Pharmacol 14:265-271, 1985
41. 10 analogues. Proc Am Ass Cancer Res 28:276, 1987
42. Jones TR, Thornton TJ, Flinn A, Jackman AL, Newell DR, Calvert AH: Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency. J Med Chem 32:847-852, 1989
43. 10-propargyl-5,8-dideazafolic acid and related compounds in mutine (L1210) and human (W1L2) systems in vitro and in L1210 in vivo. Cancer Res 50:5212-5218, 1990
44. Harrap KR, Jackman AL, Newell DR, Taylor GA, Hughes LR, Calvert AH: Thymidylate synthase, a target for anticancer drug design. In: Weber G (ed) Advances in Enzyme Regulation. Pergamon Press, New York, 1989, Vol 29, pp 161-179
45. 10-propargyl-5,8-dideazafolic acid (CB3717) polyglutamates in L1210 cells in vitro. Biochem Pharmacol 37:4047-4054, 1988
46. 10-propargyl-5,8-dideazafolic acid and their enzyme inhibition. J Med Chem 32:160-165, 1989
47. Yalowich JC, Kalman TI: Rapid determination of thymidylate synthase activity and its inhibition in intact L1210 leukemia cells in vitro. Biochem Pharmacol 34:2319-2324, 1985
48. Hughes LR, Marsham PR, Oldfield J, Jones TR, O'Connor BM, Bishop JAM, Calvert AH, Jackman AL: Thymidylate synthase (TS) inhibitory and cytotoxic activity of a series of C2 substituted-5,8-deazafolates. Proc Am Ass Cancer Res 29:286, 1988
49. Hughes LR, Jackman AL, Oldfield J, Smith RC, Burrows KD, Marsham PR, Bishop JAM, Jones TR, O'Connor BM, Calvert AH: Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C2 position. J Med Chem 33:3060-3067, 1990
50. 10-propargyl-5,8-dideazafolic acid (ICI 198583). Biochem Pharmacol 42:1885-1895, 1991
51. 10-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C2 position. J Med Chem 33:3067-3071, 1990
52. Marsham PR, Jackman AL, Oldfield J, Hughes LR, Thornton TJ, Bisset GMF, O'Connor BM, Bishop JAM, Calvert AH: Quinazoline antifolate thymidylate synthase inhibitors: benzoyl ring modifications in the C2-methyl series. J Med Chem 33:3072-3078, 1990
53. Jackman AL, Kimbell R, Brown M, Brunton L, Bisset GMF, Bavetsias V, Marscham P, Hughes LR, Boyle FT: Quinazoline-based thymidylate synthase inhibitors: relationship between structural modifications and polyglutamation. Anticancer Drug Design 10:573-589, 1995
54. Jackman AL, Kimbell R, Brown M, Brunton L, Boyle FT: Quinazoline thymidylate synthase inhibitors: methods for assessing the contribution of polyglutamation to their in vitro activity. Anticancer Drug Design 10:555-572, 1995
55. Sirotnak FM, DeGraw JI, Moccio DM, Samuels LL, Goutas L: New folate analogues of the 10-deaza-aminopterin series. Basis for structural design and biochemical and pharmacologic properties. Cancer Chemother Pharmacol 12:18-25, 1984
56. Poser RG, Sirotnak FM, Chello PL: Differential synthesis of methotrexate polyglutamates in normal proliferative and neoplastic mouse tissues in vivo. Cancer Res 41:4441-4446, 1981
57. Fry DW, Andersen LA, Borst M, Goldman ID: Analysis of the role of membrane transport in gut and Ehrlich tumor in vivo as factors in drug sensitivity and selectivity. Cancer Res 43:1087-1092, 1983
58. Marsham PR, Hughes LR, Jackman AL, Hayter AJ, Oldfield J, Wardleworth JM, Bishop JA, O'Connor BM, Calvert AH: Quinazoline antifolate thymidylate synthase inhibitors: heterocyclic benzoyl ring modifications. J Med Chem 34:1594-1605, 1991
59. 10-substituted-5,8-dideazafolates. Adv Enz Regul 31:13-27, 1991
60. Kelland LR, Kimbell R, Hardcastle A, Aherne GW, Jackman AL: Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines. Europ J Cancer 31A:981-986, 1995
61. Jackman AL, Kelland LR, Kimbell R, Brown M, Gibson W, Aherne GW, Hardcastle A, Boyle FT: Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor, ZD1694 (Tomudex) in one mouse and three human cell lines. Brit J Cancer 71:914-924, 1995
62. 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 48:459-171, 1995
63. 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, 1991
64. Gibson W, Bisset GMF, Marsham PR, Kelland LR, Judson IR, Jackman AL: The measurement of polyglutamate metabolites of the thymidylate synthase inhibitor, ICI D1694, in mouse and human cultured cells. Biochem Pharmacol 45:863-869, 1993
65. Jackman AL, Gibson W, Brown M, Kimbell R, Boyle FT: The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D1694. In: Rustum Y (ed) Proceedings of the International Symposium on Novel Approaches to Selective Treatments of Human Solid Tumors: Laboratory and Clinical Correlation. Adv Exptl Med Biol. Plenum Press, New York, 1993, Vol 339, pp 265-276
66. Takemura Y, Gibson W, Kimbell R, Kobayashi H, Miyachi H, Jackman AL: Cellular pharmacokinetics of ZD1694 in cultured human leukaemia cells sensitive, or made resistant to this drug. J Cancer Res Clin Oncol 122:109-117, 1996
67. Takemura Y, Kobayashi H, Gibson W, Kimbell R, Miyachi H, Jackman AL: The influence of drug-exposure conditions on the development of resistance to methotrexate or ZD1694 in cultured human leukaemia cells. Int J Cancer 66:29-36, 1996
68. Ward WHJ, Kimbell R, Jackman AL: Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase. Biochem Pharmacol 43:2029-2031, 1992
69. Stephens TS, Calvete JA, Janes D, Waterman SE, Valcaccia BE, Hughes LR, Calvert AH: Antitumour activity of the new thymidylate synthase inhibitor, D1694. Proc Amer Assoc Cancer Res 31:342, 1990
70. Jackman AL, Farrugia DC, Gibson W, Kimbell R, Harrap KR, Stephens TC, Azab M, Boyle FT: ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer. Europ J Cancer 31A:1277-1282, 1995
71. Jodrell DI, Newell DR, Gibson W, Hughes LR, Calvert AH: The pharmacokinetics of the quinazoline antifolate ICI D1694 in mice and rats. Cancer Chemother Pharmacol 28:331-338, 1991
72. Jackman AL, Jodrell DI, Gibson W, Stephens TC: ICI D1694, an inhibitor of thymidylate synthase for clinical study. In: Harkness RA (ed) Purine and Pyrimidine Metabolism in Man VII, Part A. Plenum Press, New York, 1991, pp 19-23
73. Stephens TC, Valcaccia BE, Sheadeer ML, Hughes LR, Jackman AL: The TS inhibitor ICI D1694 is superior to CB3717, 5-fluorouracil and methrotrexate against a panel of human tumour xenografts. Proc Amer Assoc Cancer Res 32:328, 1991
74. Jackman AL, Farrugia DC, Clarke SJ, Aherne GW, Boyle FT, Seymour L, Azab M, Kennealy G: Delayed rescue of ZD1694 toxicity in Balb/c mice with thymidine or leucovorin. Proc Amer Assoc Cancer Res 36:377, 1995
75. Clarke SJ, Jackman AL, Judson IR: The toxicity of ICI D1694 in man and mouse. In: Ayling JE, Nair MG, Baugh CM (eds) Chemistry and Biology of Pteridines and Folates. Advances in Experimental Medicine and Biology. Plenum Press, New York, 1993, Vol 338, pp 601-604
76. Jodrell DI, Newell DR, Calvete JA, Stephens TC, Calvert AH: Pharmacokinetic and toxicity studies with the novel quinazoline thymidylate synthase inhibitor, D1694. Proc Amer Assoc Cancer Res 31:341, 1990
77. 10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice. Brit J Cancer 64:833-838, 1991
78. Clarke SJ, Hanwell J, de Boer M, Planting A, Verweij J, Walker M, Smith R, Jackman AL, Hughes LR, Harrap KR, Kennealey GT, Judson IR: Phase I trial of ZD1694 (Tomudex), a new folate based, thymidylate synthase inhibitor. J Clin Oncol (in press)
79. Cunningham D, Zalcberg J, Smith IE et al.: Tomudex: a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. Ann Oncol 5(suppl 8):179, 1994
80. Zalcberg J, Cunningham D, Green M et al.: The results of a large phase II study of the potent TS inhibitor Tomudex (ZD1694) in advanced colorectal cancer. Proc ASCO 14:204, 1995
81. 10-propargyl-5,8-dideazafolic acid) in colorectal cancer. Brit J Cancer 57:628-629, 1988
82. 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. Europ J Cancer 31A:1945-1954, 1995
83. Tomudex Product Review: Publication from Zeneca Pharmaceuticals