Two activities of the immunosuppressive metabolite of leflunomide, A77 1726: Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation

Biochemical Pharmacology

Volumn 52, Issue 4, 1996, Pages 527-534

  Xu, Xiulong ^a   Williams, James W ^a   Gong, Haihua ^a   Finnegan, Alison ^a   Chong, Anita S F ^a  

^a RUSH UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

A77 1726; Brequinar sodium; Inhibition of dihydroorotate dehydrogenase; LSTRA cells; Nucleotides; Tyrosine kinase inhibitor

Indexed keywords

DIHYDROOROTATE DEHYDROGENASE; DRUG METABOLITE; IMMUNOSUPPRESSIVE AGENT; LEFLUNOMIDE; PYRIMIDINE NUCLEOTIDE; TERIFLUNOMIDE; URIDINE;

ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL GROWTH; CELL PROLIFERATION; CONTROLLED STUDY; CYTOCHEMISTRY; ENZYME INHIBITION; LEUKEMIA CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION;

ANIMALS; BLOTTING, WESTERN; DOSE-RESPONSE RELATIONSHIP, DRUG; IMMUNOSUPPRESSIVE AGENTS; ISOXAZOLES; LEUKEMIA, EXPERIMENTAL; MICE; PROTEIN-TYROSINE KINASES; TUMOR CELLS, CULTURED; URIDINE;

EID: 0030014489     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/0006-2952(96)00303-6     Document Type: Article

References (23)

1. Chong AS-F, Finnegan A, Jiang X, Gebel H, Sankary HN, Foster P and Williams JW, Leflunomide, a novel immunosuppressive agent. The mechanism of inhibition of T cell proliferation. Transplantation 55: 1361-1366, 1993.
2. Chong AS-F, Gebel H, Finnegan A, Petraitis EE, Jiang XL, Sankary HN, Foster P and Williams JW, Leflunomide, a novel immunomodulatory agent. In vitro analyses of the mechanism of immunosuppression. Transplant Proc 25: 747-749, 1993.
3. Xu X, Williams JW, Bremer EG, Finnegan A and Chong AS-F, Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem 270: 12398-12403, 1995.
4. Cherwinski HM, Byars N, Ballaron SJ, Nakano GM, Young JM and Ransom JT, Leflunomide interferes with pyrimidine nucleotide biosynthesis. Inflam Res 44: 317-322, 1995.
5. Cherwinski HM, Cohn RG, Cheung P, Webster DJ, Xu Y-Z, Caulfield JP, Young JM, Nakano G and Ransom JT, The immunosuppresant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 275: 1043-1049, 1995.
6. Nair R, Cao W and Morris R, Molecular mechanism of suppression of arterial intimal thickening by leflunomide (LFM): Demonstration of direct antiproliferative effect on murine vascular smooth muscle cells (M-VSMC) in vitro and antagonism of action by uridine. J Heart Lung Transplant (Suppl) 554, 1995.
7. Williamson RA, Yea CM, Robson PA, Curnock AP, Gadher S, Hambleton AB, Woodward K, Bruneau J-M, Hambleton P, Moss D, Thomson TA, Spinella-Jaegle S, Morand P, Courtin O, Sautés C, Westwood R, Hercend T, Kuo EA and Ruuth E, Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem 270: 22467-22472, 1995.
8. Greene S, Watanabe K, Braatz-Trulson J and Lou L, Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol 50: 861-867, 1995.
9. lck, reveals its oncogenic potential in fibroblasts. Proc Natl Acad Sci USA 85: 4247-4251, 1988.
10. Marth JD, Peet R, Krebs EG and Perlmutter RM, A lymphocyte-specific protein tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell 43: 393-404, 1985.
11. lck. Proc Natl Acad Sci USA 88: 3977-3981, 1991.
12. Lin PH, Selinfreund R, Wakshul E and Walton W, Rapid and efficient purification of plasma membrane from cultured cells: Characterization of epidermal growth factor binding. Biochemistry 26: 731-736, 1987.
13. Hurley TR and Sefton BM, Analysis of the activity and phosphorylation of the lck protein in lymphoid cells. Oncogens 4: 265-273, 1989.
14. Dileepan KN and Kennedy J, Rapid conversion of newly-synthesized orotate to uridine-5-monophosphate by rat liver cytosolic enzyme. FEBS Lett 153: 1-5, 1983.
15. Lakaschus G and Loeffler M, Differential susceptibility of dihydroorotate dehydrogenase/oxidase to brequinar sodium (NSC 368 390) in vitro. Biochem Pharmacol 43: 1025-1030, 1992.
16. Chen S-F, Rubin RL and Dexter DL, Mechanism of action of the novel anticancer agent 6-fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3-methyl-4- quinolinecarboxylic acid sodium salt (NSC 368390): Inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Res 46: 5014-5019, 1986.
17. Chen S-F, Perrella FW, Behrens DL and Papp LM, Inhibition of dihydroorotate dehydrogenase by brequinar sodium. Cancer Res 52: 3521-3527, 1992.
18. Woo J, Lemster B, Tamura K, Starzl TE and Thomson AW, The antilymphocytic activity of brequinar sodium and its potentiation by cytidine. Effect on lymphocyte proliferation and cytokine production. Transplantation 56: 374-381, 1993.
19. Peters GJ, Schwartsmann G, Nadal JC, Laurensse EJ, van Groeningen CJ and van der Vijgh WJF, In vivo inhibition of the pyrimidine enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785, NSC 368390) in mice and patients. Cancer Res 50: 4644-4649, 1990.
20. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M and Fukami Y, Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262: 5592-5595, 1987.
21. Markovits J, Linassier C, Fosse P, Couprie J, Pierre J, Jacquemin-Sablon A, Saucier J-M, Pecq J-BL and Larsen AK, Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 49: 5111-5117, 1989.
22. Forrest TL, Ware RE, Howard T, Jaffee BD and Denning SM, Novel mechanisms of brequinar sodium immunosuppression on T cell activation. Transplantation 58: 920-926, 1994.
23. Chong AS-F, Rezai K, Gebel HM, Finnegan A, Foster P, Xu X and Williams JW, Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro. Transplantation 61: 140-145, 1996.