Control of lymphoproliferative and autoimmune disease in MRL-lpr/lpr mice by brequinar sodium: mechanisms of action.
Brequinar sodium (BQR) was originally developed as an antitumor drug and subsequently as an immunosuppressant for controlling transplant rejection. It has been widely accepted that the antitumor and immunosuppressive activities of BQR are dependent on its ability to inhibit the enzymatic activity of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine synthesis pathway. Recently, we discovered that BQR has the ability to inhibit protein tyrosine phosphorylation in anti-CD3-stimulated murine T lymphocytes and to inhibit the activity of src-related protein tyrosine kinases, p56lck and p59fyn. We examined the in vivo activities of BQR in MRL-lpr/lpr mice. We report that the dose of BQR (10 mg/kg/day) that induced anemia, controlled lymphadenopathy and inhibited autoantibody production, also selectively reduced the pyrimidine nucleotide levels in the bone marrow and in the lymph nodes. Coadministration of uridine (1000 mg/kg/day) with BQR completely normalized pyrimidine nucleotide levels in the bone marrow and lymph nodes, and prevented BQR-induced anemia. However, coadministration of uridine with BQR only partially reversed the anti-proliferative effects of BQR, and did not antagonize the inhibitory effect of BQR on autoantibody production. Finally, we report that BQR markedly reduced protein tyrosine phosphorylation in lymph nodes of MRL-lpr/lpr mice. These results collectively suggest that the control of lymphadenopathy and autoantibody production in MRL-lpr/lpr mice by BQR is only partially dependent on inhibition of pyrimidine nucleotide synthesis, and suggest a critical role for in vivo inhibition of protein tyrosine phosphorylation.
Xu
X
X
Department of General Surgery, Rush Presbyterian St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Gong
H
H
Blinder
L
L
Shen
J
J
Williams
J W
JW
Chong
A S
AS
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000032:analysis; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism; D014529:Uridine / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000032:analysis; D011798:Quinaldines
D001323:Autoantibodies; D001713:Biphenyl Compounds; D003570:Cytidine Triphosphate; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide; D014443:Tyrosine; D014529:Uridine; D014544:Uridine Triphosphate; C046943:brequinar; D011798:Quinaldines