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 a nd subsequently as an immunosuppressant for controlling transplant rej ection. It has been widely accepted that the antitumor and immunosuppr essive activities of BQR are dependent on its ability to inhibit the e nzymatic activity of dihydroorotate dehydrogenase, the fourth enzyme i n the de novo pyrimidine synthesis pathway. Recently, we discovered th at BQR has the ability to inhibit protein tyrosine phosphorylation in anti-CD3-stimulated murine T lymphocytes and to inhibit the activity o f are-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 lymphadeno pathy and inhibited autoantibody production, also selectively reduced the pyrimidine nucleotide levels in the bone marrow and in the lymph n odes. 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 effect s of BQR, and did not antagonize the inhibitory effect of BQR on autoa ntibody production. Finally, we report that BQR markedly reduced prote in tyrosine phosphorylation in lymph nodes of MRL-lpr/lpr mice. These results collectively suggest that the control of lymphadenopathy and a utoantibody production in MRL-lpr/lpr mice by BQR is only partially de pendent on inhibition of pyrimidine nucleotide synthesis, and suggest a critical role for in vivo inhibition of protein tyrosine phosphoryla tion.