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Plevitrexed

Plevitrexed is an orally bioavailable, small molecule, non-polyglutamatable, antifolate quinazoline derivative thymidine synthetase inhibitor with potential antineoplastic activity. Plevitrexed is transported into the cell via the physiological reduced folate carrier (RFC) system. Intracellularly, this agent selectively binds to the folate binding site of thymidylate synthase and inhibits thymidine synthesis, which may result in DNA synthesis inhibition and apoptosis.  Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

AstraZeneca (formerly Zeneca) is developing ZD-9331, a non-polyglutamatable thymidylate synthase inhibitor, as a potential treatment for solid tumors and other neoplasia, including colorectal tumors. ZD-9331 is being developed as both an oral and an i.v. formulation, both of which are in phase II trials as of December 1999. As of June 1998, ZD-9331 was in phase II trials for advanced colorectal and other solid tumors, with drug filings not expected until 2002. A clinical study presented at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO) demonstrated that treatment with ZD-9331 resulted in a period of intracellular 2'-deoxyuridine (dUrd) elevation, a surrogate marker of thymidylate synthase inhibition, with observed myelosuppression being no greater than that seen with raltitrexed and less than with bolus 5-FU. Results from a 56-patient phase I study were presented at the 1999 ASCO meeting. Dose escalation followed a two-stage procedure. As in previous studies myelosuppression was the dose-limiting toxicity, occurring at 4.8 and 7.5 mg/m2/day, with one patient at each of these two doses experiencing a DLT. The MTD was not achieved until 12 to 16 mg/m2/day, based on which a fixed dose of 25 mg/day was being evaluated. A number of other studies are ongoing, comparing once to twice daily dosages as well as the pharmacokinetics of the compound. Encouraging phase I data have been seen in melanoma, ovarian, colon and breast cancer; myelosuppression is the dose limiting toxicity in the majority of these studies. A phase I dose-escalation trial was conducted to evaluate the feasibility of a once 3-weekly 30-min i.v. infusion of ZD-9331, with doses ranging from 4.8 to 370 mg/m2. The regimen was overall well tolerated up to 370 mg/m2, with grade IV myelosuppression and grade IV diarrhea being observed in a small number of patients. In June 2000, Deutsche Bank predicted sales of $12 million in 2002. In January 1999, ABN Amro predicted sales of US $8 million in 2002 rising to $66 million in 2005. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach the worldwide markets, and be launched in 2002.[Source: Curr Opin Investig Drugs. 2000 Sep;1(1):141-9. or http://www.ncbi.nlm.nih.gov/pubmed/11249590].

Current developer:    BTG Oncology Inc

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2: Peña MM, Xing YY, Koli S, Berger FG. Role of N-terminal residues in the ubiquitin-independent degradation of human thymidylate synthase. Biochem J. 2006 Feb 15;394(Pt 1):355-63. PubMed PMID: 16259621; PubMed Central PMCID: PMC1386034.

3: Coudray AM, Louvet C, Kornprobst M, Raymond E, André T, Tournigand C, Faivre S, De Gramont A, Larsen AK, Gespach C. Increased anticancer activity of the thymidylate synthase inhibitor BGC9331 combined with the topoisomerase I inhibitor SN-38 in human colorectal and breast cancer cells: induction of apoptosis and ROCK cleavage through caspase-3-dependent and -independent mechanisms. Int J Oncol. 2005 Aug;27(2):553-61. PubMed PMID: 16010439.

4: Louvet C, André T, Gamelin E, Garcia ML, Saavedra A, Lenaers G, de Gramont A, Méry-Mignard D, Kalla S. A phase I-II, dose-escalating trial of ZD9331 in combination with irinotecan (CPT11) in previously pretreated metastatic colorectal cancer patients. Bull Cancer. 2004 Dec;91(12):279-84. PubMed PMID: 15634630.

5: Benepal TS, Judson I. ZD9331: discovery to clinical development. Anticancer Drugs. 2005 Jan;16(1):1-9. Review. PubMed PMID: 15613898.

6: Damaraju VL, Hamilton KF, Seth-Smith ML, Cass CE, Sawyer MB. Characterization of binding of folates and antifolates to brush-border membrane vesicles isolated from human kidney. Mol Pharmacol. 2005 Feb;67(2):453-9. Epub 2004 Oct 27. PubMed PMID: 15509714.

7: Wang Y, Zhao R, Goldman ID. Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6256-64. PubMed PMID: 15448015.

8: Geller JI, Szekely-Szucs K, Petak I, Doyle B, Houghton JA. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells. Cancer Res. 2004 Sep 1;64(17):6296-303. PubMed PMID: 15342418.

9: Ackland SP, Beale P, Peters GJ. Thymidylate synthase inhibitors. Cancer Chemother Biol Response Modif. 2003;21:1-28. Review. PubMed PMID: 15338738.

10: Schwartz GH, Jones CB, Garrison M, Patnaik A, Takimoto C, McCreery H, Skinner M, Tolcher AW, Rowinsky EK. A phase I and pharmacokinetic study of the nonpolyglutamatable thymidylate synthase inhibitor ZD9331 plus docetaxel in patients with advanced solid malignancies. Invest New Drugs. 2004 Nov;22(4):437-48. PubMed PMID: 15292714.

11: Schulz J, Keller A, Canfield V, Parker G, Douglass E. ZD9331 as second- or third-line therapy in patients with advanced colorectal cancer: a phase II multicenter trial. Am J Clin Oncol. 2004 Aug;27(4):337-42. PubMed PMID: 15289725.

12: Jackman AL, Theti DS, Gibbs DD. Antifolates targeted specifically to the folate receptor. Adv Drug Deliv Rev. 2004 Apr 29;56(8):1111-25. Review. PubMed PMID: 15094210.

13: Forsthoefel AM, Peña MM, Xing YY, Rafique Z, Berger FG. Structural determinants for the intracellular degradation of human thymidylate synthase. Biochemistry. 2004 Feb 24;43(7):1972-9. PubMed PMID: 14967037.

14: Theti DS, Jackman AL. The role of alpha-folate receptor-mediated transport in the antitumor activity of antifolate drugs. Clin Cancer Res. 2004 Feb 1;10(3):1080-9. PubMed PMID: 14871988.

15: Bilenker JH, Stevenson JP, Flaherty KT, Algazy K, McLaughlin K, Haller DG, Giantonio BJ, Koehler M, Garcia-Vargas JE, O'Dwyer PJ. Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies. Cancer Chemother Pharmacol. 2004 Apr;53(4):357-60. Epub 2004 Jan 13. PubMed PMID: 14722734.

16: Geller J, Petak I, Szucs KS, Nagy K, Tillman DM, Houghton JA. Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin. Clin Cancer Res. 2003 Dec 15;9(17):6504-15. PubMed PMID: 14695155.

17: Rader JS, Clarke-Pearson D, Moore M, Carson L, Holloway R, Kao MS, Wiznitzer I, Douglass EC. A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer. Gynecol Oncol. 2003 Nov;91(2):318-25. PubMed PMID: 14599861.

18: Benson A 3rd, Poplin E, Vergote I. ZD9331 in combination with topotecan: phase I and II experience. Anticancer Drugs. 2003 May;14 Suppl 1:S21-7. Review. PubMed PMID: 14567437.

19: Hainsworth J, Vergote I, Janssens J. A review of phase II studies of ZD9331 treatment for relapsed or refractory solid tumours. Anticancer Drugs. 2003 May;14 Suppl 1:S13-9. PubMed PMID: 14567436.

20: Petruzelka L. Phase II multicentre trial of ZD9331 monotherapy as first-line treatment for gastric cancer. Anticancer Drugs. 2003 May;14 Suppl 1:S7-12. PubMed PMID: 14567435.

21: Koizumi W, Aiba K, Sasaki T, Sato A, Horikoshi N. Phase I dose-escalation trial of ZD9331 in Japanese patients with refractory, solid malignancies. Anticancer Drugs. 2003 May;14 Suppl 1:S1-5. PubMed PMID: 14567434.

22: Smith D, Gallagher N. A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. Eur J Cancer. 2003 Jul;39(10):1377-83. PubMed PMID: 12826040.

23: 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.

24: Rees C, Beale P, Trigo JM, Mitchell F, Jackman A, Smith R, Douglass E, Judson I. Phase I trial of ZD9331, a nonpolyglutamatable thymidylate synthase inhibitor, given as a 5-day continuous infusion to patients with refractory solid malignancies. Clin Cancer Res. 2003 Jun;9(6):2049-55. PubMed PMID: 12796367.

25: Sawyer MB, Ratain MJ, Bertucci D, Smith RP, Schilsky RL, Vogelzang NJ, Shulman K, Douglass EC, Fleming GF. Phase I study of an oral formulation of ZD9331 administered daily for 28 days. J Clin Oncol. 2003 May 1;21(9):1859-65. PubMed PMID: 12721264.

26: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Jan-Feb;25(1):53-76. PubMed PMID: 12690708.

27: Plummer R, Rees C, Hughes A, Beale P, Highley M, Trigo J, Gokul S, Judson I, Calvert H, Jackman A, Mitchell F, Smith R, Douglass E. A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor. Clin Cancer Res. 2003 Apr;9(4):1313-22. PubMed PMID: 12684399.

28: Wang Y, Zhao R, Goldman ID. Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line. Biochem Pharmacol. 2003 Apr 1;65(7):1163-70. PubMed PMID: 12663051.

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

31: Welsh SJ, Hobbs S, Aherne GW. Expression of uracil DNA glycosylase (UDG) does not affect cellular sensitivity to thymidylate synthase (TS) inhibition. Eur J Cancer. 2003 Feb;39(3):378-87. PubMed PMID: 12565992.

32: Liani E, Rothem L, Bunni MA, Smith CA, Jansen G, Assaraf YG. Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99. PubMed PMID: 12494465.

33: Rose MG, Farrell MP, Schmitz JC. Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer. 2002 Feb;1(4):220-9. Review. PubMed PMID: 12450420.

34: D'Orazio AI, Gambill BD. 25th European Society for Medical Oncology Congress. Hamburg, Germany. October 13-17, 2000. Clin Colorectal Cancer. 2001 May;1(1):10-5. PubMed PMID: 12445373.

35: Wang Y, Zhao R, Chattopadhyay S, Goldman ID. A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed. Cancer Res. 2002 Nov 15;62(22):6434-7. Erratum in: Cancer Res. 2003 Oct 15;63(20):7004. PubMed PMID: 12438230.

36: de Jonge MJ, Glimelius B, Verweij J, Van Groeningen C, Bonneterre J, de Vries EG, Culine S, Young J, Smith R, Droz J. Effects of impaired renal function on the pharmacokinetics and toxicity of i.v. ZD9331, a novel non-polyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. Anticancer Drugs. 2002 Jul;13(6):645-53. PubMed PMID: 12172511.

37: Rothem L, Ifergan I, Kaufman Y, Priest DG, Jansen G, Assaraf YG. Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukaemia cell lines. Biochem J. 2002 Nov 1;367(Pt 3):741-50. PubMed PMID: 12139489; PubMed Central PMCID: PMC1222927.

38: Jackman AL, Melin CJ, Kimbell R, Brunton L, Aherne GW, Theti DS, Walton M. A rationale for the clinical development of the thymidylate synthase inhibitor ZD9331 in ovarian and other solid tumours. Biochim Biophys Acta. 2002 Jul 18;1587(2-3):215-23. Review. PubMed PMID: 12084463.

39: Longley DB, Boyer J, Allen WL, Latif T, Ferguson PR, Maxwell PJ, McDermott U, Lynch M, Harkin DP, Johnston PG. The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. Cancer Res. 2002 May 1;62(9):2644-9. PubMed PMID: 11980662.

40: de Jonge MJ, Punt CJ, Sparreboom A, Planting AS, Peters ME, van De Schraaf J, Jackman A, Smith R, de Mulder PH, Verweij J. Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors. J Clin Oncol. 2002 Apr 1;20(7):1923-31. PubMed PMID: 11919253.

41: Mauritz R, Peters GJ, Priest DG, Assaraf YG, Drori S, Kathmann I, Noordhuis P, Bunni MA, Rosowsky A, Schornagel JH, Pinedo HM, Jansen G. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol. 2002 Jan 15;63(2):105-15. PubMed PMID: 11841783.

42: Ford HE, Mitchell F, Cunningham D, Farrugia DC, Hill ME, Rees C, Calvert AH, Judson IR, Jackman AL. Patterns of elevation of plasma 2'-deoxyuridine, a surrogate marker of thymidylate synthase (TS) inhibition, after administration of two different schedules of 5-fluorouracil and the specific TS inhibitors raltitrexed (Tomudex) and ZD9331. Clin Cancer Res. 2002 Jan;8(1):103-9. PubMed PMID: 11801545.

43: Longley DB, Ferguson PR, Boyer J, Latif T, Lynch M, Maxwell P, Harkin DP, Johnston PG. Characterization of a thymidylate synthase (TS)-inducible cell line: a model system for studying sensitivity to TS- and non-TS-targeted chemotherapies. Clin Cancer Res. 2001 Nov;7(11):3533-9. PubMed PMID: 11705873.

44: Aherne GW, Hardcastle A, Ward E, Dobinson D, Crompton T, Valenti M, Brunton L, Jackman AL. Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules. Clin Cancer Res. 2001 Sep;7(9):2923-30. PubMed PMID: 11555611.

45: Webley SD, Welsh SJ, Jackman AL, Aherne GW. The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition. Br J Cancer. 2001 Aug 3;85(3):446-52. PubMed PMID: 11487279; PubMed Central PMCID: PMC2364072.

46: Zhao R, Gao F, Goldman ID. Marked suppression of the activity of some, but not all, antifolate compounds by augmentation of folate cofactor pools within tumor cells. Biochem Pharmacol. 2001 Apr 1;61(7):857-65. PubMed PMID: 11274972.

47: Niculescu-Duvaz I. ZD-9331 AstraZeneca. Curr Opin Investig Drugs. 2000 Sep;1(1):141-9. Review. PubMed PMID: 11249590.

48: Goh BC, Ratain MJ, Bertucci D, Smith R, Mani S, Vogelzang NJ, Schilsky RL, Hutchison M, Smith M, Averbuch S, Douglass E. Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations. J Clin Oncol. 2001 Mar 1;19(5):1476-84. PubMed PMID: 11230494.

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

50: Mitchell F, Lynn S, Jackman AL. Modified high-performance liquid chromatography assay for the measurement of 2'-deoxyuridine in human plasma and its application to pharmacodynamic studies of antimetabolite drugs. J Chromatogr B Biomed Sci Appl. 2000 Jul 21;744(2):351-8. PubMed PMID: 10993524.

51: Backus HH, Pinedo HM, Wouters D, Padrón JM, Molders N, van Der Wilt CL, van Groeningen CJ, Jansen G, Peters GJ. Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer. 2000 Sep 15;87(6):771-8. PubMed PMID: 10956384.

52: Webley SD, Hardcastle A, Ladner RD, Jackman AL, Aherne GW. Deoxyuridine triphosphatase (dUTPase) expression and sensitivity to the thymidylate synthase (TS) inhibitor ZD9331. Br J Cancer. 2000 Sep;83(6):792-9. PubMed PMID: 10952785; PubMed Central PMCID: PMC2363540.

53: Rode W, Dabrowska M, Zieliński Z, Gołos B, Wranicz M, Felczak K, Kulikowski T. Trichinella spiralis and Trichinella pseudospiralis: developmental patterns of enzymes involved in thymidylate biosynthesis and pyrimidine salvage. Parasitology. 2000 Jun;120 ( Pt 6):593-600. PubMed PMID: 10874722.

54: 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.

55: 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.

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

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

58: Rots MG, Pieters R, Peters GJ, van Zantwijk CH, Mauritz R, Noordhuis P, Willey JC, Hählen K, Creutzig U, Janka-Schaub G, Kaspers GJ, Veerman AJ, Jansen G. Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. Blood. 1999 Nov 1;94(9):3121-8. PubMed PMID: 10556198.

59: Marsham PR, Wardleworth JM, Boyle FT, Hennequin LF, Kimbell R, Brown M, Jackman AL. Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors. J Med Chem. 1999 Sep 23;42(19):3809-20. PubMed PMID: 10508430.

60: Walton MI, Mitchell F, Aherne GW, Medlow CJ, Boyle FT, Jackman AL. The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice. Br J Cancer. 1998 Dec;78(11):1457-63. PubMed PMID: 9836478; PubMed Central PMCID: PMC2063203.

61: Faessel HM, Slocum HK, Jackson RC, Boritzki TJ, Rustum YM, Nair MG, Greco WR. Super in vitro synergy between inhibitors of dihydrofolate reductase and inhibitors of other folate-requiring enzymes: the critical role of polyglutamylation. Cancer Res. 1998 Jul 15;58(14):3036-50. PubMed PMID: 9679969.

62: 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.

63: Kobayashi H, Takemura Y, Miyachi H. Molecular characterization of human acute leukemia cell line resistant to ZD9331, a non-polyglutamatable thymidylate synthase inhibitor. Cancer Chemother Pharmacol. 1998;42(2):105-10. PubMed PMID: 9654109.

64: Kobayashi H, Takemura Y, Ohnuma T. Variable expression of RFC1 in human leukemia cell lines resistant to antifolates. Cancer Lett. 1998 Feb 27;124(2):135-42. PubMed PMID: 9500202.

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

66: Jackman AL, Kimbell R, Aherne GW, Brunton L, Jansen G, Stephens TC, Smith MN, Wardleworth JM, Boyle FT. Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331: a water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. Clin Cancer Res. 1997 Jun;3(6):911-21. PubMed PMID: 9815766.

67: Brandt DS, Chu E. Future challenges in the clinical development of thymidylate synthase inhibitor compounds. Oncol Res. 1997;9(8):403-10. PubMed PMID: 9436193.

68: Drake JC, Allegra CJ, Moran RG, Johnston PG. Resistance to tomudex (ZD1694): multifactorial in human breast and colon carcinoma cell lines. Biochem Pharmacol. 1996 May 17;51(10):1349-55. PubMed PMID: 8787551.

69: Touroutoglou N, Pazdur R. Thymidylate synthase inhibitors. Clin Cancer Res. 1996 Feb;2(2):227-43. Review. PubMed PMID: 9816165.

70: Van Cutsem E. A glimpse of the future. new directions in the treatment of colorectal cancer. Eur J Cancer. 1996;32A Suppl 5:S23-7. Review. PubMed PMID: 8958039.

71: Jackman AL, Calvert AH. Folate-based thymidylate synthase inhibitors as anticancer drugs. Ann Oncol. 1995 Nov;6(9):871-81. Review. PubMed PMID: 8624289.

72: Kobayashi H, Takemura Y, Miyachi H, Skelton L, Jackman AL. Effect of hammerhead ribozyme against human thymidylate synthase on the cytotoxicity of thymidylate synthase inhibitors. Jpn J Cancer Res. 1995 Nov;86(11):1014-8. PubMed PMID: 8567390.

73: Harrap KR. Initiatives with platinum- and quinazoline-based antitumor molecules--Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 1995 Jul 1;55(13):2761-8. Review. PubMed PMID: 7796401.

74: Aherne W, Hardcastle A, Kelland L, Jackman A. The measurement of deoxynucleotide (dNTP) pools by radioimmunoassay (RIA). Adv Exp Med Biol. 1994;370:801-4. PubMed PMID: 7661027.

75: Jackman AL, Kimbell R, Brown M, Brunton L, Harrap KR, Wardleworth JM, Boyle FT. The antitumour activity of ZD9331, a non-polyglutamatable quinazoline thymidylate synthase inhibitor. Adv Exp Med Biol. 1994;370:185-8. Review. PubMed PMID: 7660886.