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Nolatrexed

nolatrexed dihydrochloride is the dihydrochloride salt of nolatrexed, a water-soluble lipophilic quinazoline folate analog with antineoplastic activity. Nolatrexed occupies the folate binding site of thymidylate synthase, resulting in inhibition of thymidylate synthase activity and thymine nucleotide synthesis with subsequent inhibition of DNA replication, DNA damage, S-phase cell cycle arrest, and caspase-dependent apoptosis. This agent also exhibits radiosensitizing activity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Eximias Pharmaceutical (Orphan Drug), Agouron (Originator), Eximias Pharmaceutical (Licensee), LG Chem (Licensee).

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2: Wang GF, Zhang JY, Wu SY, Xu W, Wan SH, Shao CF, Zhang JJ. [Measurement of plasma concentration and bioavailability of nolatrexed dihydrochloride in mice]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Nov;28(11):1993-5. Chinese. PubMed PMID: 19033111.

3: Chen SZ, Wang SM, Zhang JR. [Preparation of long-circulating nolatrexed dihydrochloride liposomes and its antitumor activity]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Mar;28(3):403-5. Chinese. PubMed PMID: 18359701.

4: Gangjee A, Jain HD, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II. Anticancer Agents Med Chem. 2008 Feb;8(2):205-31. Review. PubMed PMID: 18288923.

5: Gangjee A, Jain HD, Kurup S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. Anticancer Agents Med Chem. 2007 Sep;7(5):524-42. Review. PubMed PMID: 17896913.

6: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.

7: Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007 Jul 20;25(21):3069-75. PubMed PMID: 17634485.

8: Giovannetti E, Backus HH, Wouters D, Ferreira CG, van Houten VM, Brakenhoff RH, Poupon MF, Azzarello A, Pinedo HM, Peters GJ. Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer. 2007 Mar 12;96(5):769-75. PubMed PMID: 17339891; PubMed Central PMCID: PMC2360080.

9: Jhawer M, Rosen L, Dancey J, Hochster H, Hamburg S, Tempero M, Clendeninn N, Mani S. Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2007 Feb;25(1):85-94. Epub 2006 Sep 7. PubMed PMID: 16957834.

10: Bram E, Ifergan I, Shafran A, Berman B, Jansen G, Assaraf YG. Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. Cancer Chemother Pharmacol. 2006 Dec;58(6):826-34. Epub 2006 Apr 13. PubMed PMID: 16612649.

11: Yau K, Price P, Pillai RG, Aboagye E. Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors. Eur J Nucl Med Mol Imaging. 2006 Sep;33(9):981-7. Epub 2006 Mar 28. PubMed PMID: 16568206.

12: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2005 May;27(4):265-84. PubMed PMID: 16082427.

13: Temmink OH, Hoogeland MF, Fukushima M, Peters GJ. Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9. Epub 2005 Jul 12. PubMed PMID: 16010590.

14: Hu M, Chen J. Nucleobase- and p-glycoprotein-mediated transport of AG337 in a Caco-2 cell culture model. Mol Pharm. 2004 May-Jun;1(3):194-200. PubMed PMID: 15981922.

15: Li YL, Wu SG. [Effects of nolatrexed on thymidylate synthase protein expression]. Di Yi Jun Yi Da Xue Xue Bao. 2004 Aug;24(8):881-4. Chinese. PubMed PMID: 15321751.

16: Sakoff JA, Howitt IJ, Ackland SP, McCluskey A. Serine/threonine protein phosphatase inhibition enhances the effect of thymidylate synthase inhibition. Cancer Chemother Pharmacol. 2004 Mar;53(3):225-32. Epub 2003 Nov 25. PubMed PMID: 14648018.

17: Chu E, Callender MA, Farrell MP, Schmitz JC. Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol. 2003 Jul;52 Suppl 1:S80-9. Epub 2003 Jun 18. Review. PubMed PMID: 12819937.

18: Wells P, Aboagye E, Gunn RN, Osman S, Boddy AV, Taylor GA, Rafi I, Hughes AN, Calvert AH, Price PM, Newell DR. 2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337. J Natl Cancer Inst. 2003 May 7;95(9):675-82. PubMed PMID: 12734319.

19: Purcell WT, Ettinger DS. Novel antifolate drugs. Curr Oncol Rep. 2003 Mar;5(2):114-25. Review. PubMed PMID: 12583828.

20: Wu Q, Dolnick BJ. Detection of thymidylate synthase modulators by a novel screening assay. Mol Pharmacol. 2003 Jan;63(1):167-73. PubMed PMID: 12488549.

21: Marsh S, McLeod HL. Thymidylate synthase pharmacogenetics in colorectal cancer. Clin Colorectal Cancer. 2001 Nov;1(3):175-8; discussion 179-81. Review. PubMed PMID: 12450432.

22: van der Wilt CL, Smid K, Peters GJ. Effects of antifolates on the binding of 5-fluoro-2'-deoxyuridine monophosphate to thymidylate synthase. Biochem Pharmacol. 2002 Aug 15;64(4):669-75. PubMed PMID: 12167486.

23: Pivot X, Wadler S, Kelly C, Ruxer R, Tortochaux J, Stern J, Belpomme D, Humblet Y, Domenge C, Clendeninn N, Johnston A, Penning C, Schneider M. Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer. Ann Oncol. 2001 Nov;12(11):1595-9. PubMed PMID: 11822760.

24: Backus HH, Wouters D, van der Wilt CL, Kuiper CM, van Groeningen CJ, Pinedo HM, Peters GJ. Thymidylate synthase inhibition induces p53 dependent and independent cell death. Adv Exp Med Biol. 2000;486:303-6. PubMed PMID: 11783505.

25: Longo GS, Izzo J, Gorlick R, Banerjee D, Jhanwar SC, Bertino JR. Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase. Oncol Res. 2001;12(8):309-14. PubMed PMID: 11589301.

26: Niculescu-Duvaz I. Thymitaq (Zarix). Curr Opin Investig Drugs. 2001 May;2(5):693-705. Review. PubMed PMID: 11569949.

27: Backus HH, Pinedo HM, Wouters D, Kuiper CM, Jansen G, van Groeningen CJ, Peters GJ. Differences in the induction of DNA damage, cell cycle arrest, and cell death by 5-fluorouracil and antifolates. Oncol Res. 2000;12(5):231-9. PubMed PMID: 11417748.

28: Chi KH, Wang HE, Chen FD, Chao Y, Liu RS, Chou SL, Wang YS, Yen SH. Preclinical evaluation of locoregional delivery of radiolabeled iododeoxyuridine and thymidylate synthase inhibitor in a hepatoma model. J Nucl Med. 2001 Feb;42(2):345-51. PubMed PMID: 11216535.

29: Estlin EJ, Pinkerton CR, Lewis IJ, Lashford L, McDowell H, Morland B, Kohler J, Newell DR, Boddy AV, Taylor GA, Price L, Ablett S, Hobson R, Pitsiladis M, Brampton M, Clendeninn N, Johnston A, Pearson AD. A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation. Br J Cancer. 2001 Jan 5;84(1):11-8. PubMed PMID: 11139306; PubMed Central PMCID: PMC2363615.

30: Sakoff JA, Ackland SP. Thymidylate synthase inhibition induces S-phase arrest, biphasic mitochondrial alterations and caspase-dependent apoptosis in leukaemia cells. Cancer Chemother Pharmacol. 2000;46(6):477-87. PubMed PMID: 11138461.

31: Cassidy J. Thymidylate synthase inhibitors in colorectal cancer. Semin Oncol. 2000 Oct;27(5 Suppl 10):83-7. Review. PubMed PMID: 11049037.

32: Drori S, Jansen G, Mauritz R, Peters GJ, Assaraf YG. Clustering of mutations in the first transmembrane domain of the human reduced folate carrier in GW1843U89-resistant leukemia cells with impaired antifolate transport and augmented folate uptake. J Biol Chem. 2000 Oct 6;275(40):30855-63. PubMed PMID: 10899164.

33: Welsh SJ, Titley J, Brunton L, Valenti M, Monaghan P, Jackman AL, Aherne GW. Comparison of thymidylate synthase (TS) protein up-regulation after exposure to TS inhibitors in normal and tumor cell lines and tissues. Clin Cancer Res. 2000 Jun;6(6):2538-46. PubMed PMID: 10873110.

34: Strømhaug A, Warren DJ. A comparison of the effects of nine folate analogs on early and late murine hematopoietic progenitor cells in vitro. Cancer Chemother Pharmacol. 2000;45(6):450-6. PubMed PMID: 10854131.

35: Van Triest B, Pinedo HM, Giaccone G, Peters GJ. Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors. Ann Oncol. 2000 Apr;11(4):385-91. Review. PubMed PMID: 10847455.

36: van der Wilt CL, Kuiper CM, Peters GJ. Combination studies of antifolates with 5-fluorouracil in colon cancer cell lines. Oncol Res. 1999;11(8):383-91. PubMed PMID: 10803742.

37: Hughes AN, Griffin MJ, Newell DR, Calvert AH, Johnston A, Kerr B, Lee C, Liang B, Boddy AV. Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, Thymitaq) and paclitaxel. Br J Cancer. 2000 May;82(9):1519-27. PubMed PMID: 10789718; PubMed Central PMCID: PMC2363406.

38: Fantz C, Shaw D, Jennings W, Forsthoefel A, Kitchens M, Phan J, Minor W, Lebioda L, Berger FG, Spencer HT. Drug-resistant variants of Escherichia coli thymidylate synthase: effects of substitutions at Pro-254. Mol Pharmacol. 2000 Feb;57(2):359-66. PubMed PMID: 10648646.

39: Danenberg PV, Malli H, Swenson S. Thymidylate synthase inhibitors. Semin Oncol. 1999 Dec;26(6):621-31. Review. PubMed PMID: 10606255.

40: Newell DR. Clinical pharmacokinetics of antitumor antifolates. Semin Oncol. 1999 Apr;26(2 Suppl 6):74-81. Review. PubMed PMID: 10598559.

41: Rastogi S, Zamansky I, Roy S, Tyle P, Suryanarayanan R. Solid-state phase transitions of AG337, an antitumor agent. Pharm Dev Technol. 1999;4(4):623-32. PubMed PMID: 10578517.

42: McGuire JJ, Canestrari JG, Nagel GS. Characterization of the effect of AG337, a novel lipophilic thymidylate synthase inhibitor, on human head and neck and human leukemia cell lines. Int J Oncol. 1999 Dec;15(6):1245-50. PubMed PMID: 10568835.

43: Barnes MJ, Estlin EJ, Taylor GA, Aherne GW, Hardcastle A, McGuire JJ, Calvete JA, Lunec J, Pearson AD, Newell DR. Impact of polyglutamation on sensitivity to raltitrexed and methotrexate in relation to drug-induced inhibition of de novo thymidylate and purine biosynthesis in CCRF-CEM cell lines. Clin Cancer Res. 1999 Sep;5(9):2548-58. PubMed PMID: 10499632.

44: Curtin NJ, Bowman KJ, Turner RN, Huang B, Loughlin PJ, Calvert AH, Golding BT, Griffin RJ, Newell DR. Potentiation of the cytotoxicity of thymidylate synthase (TS) inhibitors by dipyridamole analogues with reduced alpha1-acid glycoprotein binding. Br J Cancer. 1999 Aug;80(11):1738-46. PubMed PMID: 10468290; PubMed Central PMCID: PMC2363125.

45: Mok TS, Leung TW, Lee SD, Chao Y, Chan AT, Huang A, Lui MC, Yeo W, Chak K, Johnston A, Johnson P. A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 1999;44(4):307-11. PubMed PMID: 10447578.

46: Sapse DS, Tong Y, Bertino JR, Sapse AM. Ab initio studies of some amino acid residue complexes with 4-mercaptopyridine as a model for thymitaq (AG337), an inhibitor of thymidylate synthase. Cancer Invest. 1999;17(6):396-401. PubMed PMID: 10434950.

47: Stuart K, Tessitore J, Rudy J, Clendennin N, Johnston A. A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma. Cancer. 1999 Aug 1;86(3):410-4. PubMed PMID: 10430248.

48: Jodrell DI, Bowman A, Rye R, Byrne B, Boddy A, Rafi I, Taylor GA, Johnston A, Clendeninn NJ. A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration. Br J Cancer. 1999 Feb;79(5-6):915-20. PubMed PMID: 10070890; PubMed Central PMCID: PMC2362691.

49: Hughes AN, Rafi I, Griffin MJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV. Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res. 1999 Jan;5(1):111-8. PubMed PMID: 9918208.

50: Kim SH, Brown SL, Kim JH. The potentiation of radiation response in human colon carcinoma cells in vitro and murine lymphoma in vivo by AG337 (Thymitaq), a novel thymidylate synthase inhibitor. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):789-93. PubMed PMID: 9845097.

51: Bowman KJ, White A, Golding BT, Griffin RJ, Curtin NJ. Potentiation of anti-cancer agent cytotoxicity by the potent poly(ADP-ribose) polymerase inhibitors NU1025 and NU1064. Br J Cancer. 1998 Nov;78(10):1269-77. PubMed PMID: 9823965; PubMed Central PMCID: PMC2063197.

52: Tong Y, Liu-Chen X, Ercikan-Abali EA, Zhao SC, Banerjee D, Maley F, Bertino JR. Probing the folate-binding site of human thymidylate synthase by site-directed mutagenesis. Generation of mutants that confer resistance to raltitrexed, Thymitaq, and BW1843U89. J Biol Chem. 1998 Nov 20;273(47):31209-14. PubMed PMID: 9813027.

53: Bavetsias V, Jackman AL. Nonpolyglutamatable antifolates as inhibitors of thymidylate synthase (TS) and potential antitumour agents. Curr Med Chem. 1998 Aug;5(4):265-88. Review. PubMed PMID: 9668195.

54: Hu M, Roland K, Ge L, Chen J, Li Y, Tyle P, Roy S. Determination of absorption characteristics of AG337, a novel thymidylate synthase inhibitor, using a perfused rat intestinal model. J Pharm Sci. 1998 Jul;87(7):886-90. PubMed PMID: 9649359.

55: Tong Y, Liu-Chen X, Ercikan-Abali EA, Capiaux GM, Zhao SC, Banerjee D, Bertino JR. Isolation and characterization of thymitaq (AG337) and 5-fluoro-2-deoxyuridylate-resistant mutants of human thymidylate synthase from ethyl methanesulfonate-exposed human sarcoma HT1080 cells. J Biol Chem. 1998 May 8;273(19):11611-8. PubMed PMID: 9565579.

56: Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH. Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131-41. PubMed PMID: 9508200.

57: Creaven PJ, Pendyala L, Meropol NJ, Clendeninn NJ, Wu EY, Loewen GM, Proefrock A, Johnston A, Dixon M. Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol. 1998;41(2):167-70. PubMed PMID: 9443631.

58: Takimoto CH. Antifolates in clinical development. Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-40-S18-51. Review. PubMed PMID: 9420020.

59: Li S, Zamansky I, Orlov I, Tyle P, Roy SD. Preformulation studies for the development of a parenteral liquid formulation of an antitumor agent, AG337. PDA J Pharm Sci Technol. 1997 Sep-Oct;51(5):181-6. PubMed PMID: 9357303.

60: van Triest B, Pinedo HM, Telleman F, van der Wilt CL, Jansen G, Peters GJ. Cross-resistance to antifolates in multidrug resistant cell lines with P-glycoprotein or multidrug resistance protein expression. Biochem Pharmacol. 1997 Jun 15;53(12):1855-66. PubMed PMID: 9256160.

61: Dash AK, Tyle P. Solid-state characterization of AG337 (Thymitaq), a novel antitumor drug. J Pharm Sci. 1996 Oct;85(10):1123-7. PubMed PMID: 8897283.

62: Raymond E, Djelloul S, Buquet-Fagot C, Mester J, Gespach C. Synergy between the non-classical thymidylate synthase inhibitor AG337 (Thymitaq) and cisplatin in human colon and ovarian cancer cells. Anticancer Drugs. 1996 Sep;7(7):752-7. PubMed PMID: 8949986.

63: Mester J, DeGoeij K, Sluyser M. Modulation of [5-125I]iododeoxyuridine incorporation into tumour and normal tissue DNA by methotrexate and thymidylate synthase inhibitors. Eur J Cancer. 1996 Aug;32A(9):1603-8. PubMed PMID: 8911125.

64: Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol. 1996;37(6):509-17. PubMed PMID: 8612303.

65: Rafi I, Taylor GA, Calvete JA, Boddy AV, Balmanno K, Bailey N, Lind M, Calvert AH, Webber S, Jackson RC, et al. Clinical pharmacokinetic and pharmacodynamic studies with the nonclassical antifolate thymidylate synthase inhibitor 3, 4-dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolone dihydrochloride (AG337) given by 24-hour continuous intravenous infusion. Clin Cancer Res. 1995 Nov;1(11):1275-84. PubMed PMID: 9815922.