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In Vitro and In Vivo Mechanisms of Action of the Antiproliferative and Immunosuppressive Agent, Brequinar Sodium¹

Xiulong Xu^*, James W. Williams^*, Jikun Shen^*, Haihua Gong^*, Deng-Ping Yin^*, Leonard Blinder^*, Robert T. Elder^*, Howard Sankary^*, Alison Finnegan^, and Anita S.-F. Chong^2,*,

Departments of ^* General Surgery and Immunology/Microbiology and Section of Rheumatology, Department of Internal Medicine, Rush Medical College, Chicago, IL 60612

Intracellular pyrimidine nucleotides (PyN) can be synthesized de novo from glutamine, CO₂, and ATP, or they can be salvaged from preformed pyrimidine nucleosides. The antiproliferative and immunosuppressive activities of brequinar sodium (BQR) are thought to be due to the inhibition of the activity of dihydroorotate dehydrogenase, which results in a suppression of de novo pyrimidine synthesis. Here we describe the effects of the pyrimidine nucleoSide, uridine, on the antiproliferative and immunosuppressive activities of BQR. In vitro reduction of PyN levels in Con A-stimulated T cells and inhibition of cell proliferation by low concentrations of BQR (65 µM) are reversed by uridine. However, uridine is unable to reverse the effects of high concentrations of BQR (65 µM). The ability of BQR to induce anemia in BALB/c mice is prevented by the coadministration of uridine. In contrast, the immunosuppressive activity of BQR is unaffected by similar doses of uridine. PyN levels in the bone marrow, but not in the spleen, are depressed in mice treated with BQR. These observations suggest that the induction of anemia by BQR is due to depletion of intracellular PyN in hemopoietic stem cells located in the bone marrow. They also suggest that the mechanism of immunosuppression by BQR may be only marginally dependent on depletion of intracellular PyN in lymphocytes located in the periphery. We report a novel activity of BQR: inhibition of tyrosine phosphorylation, and hypothesize that the immunosuppressive activity may be due, in part, to this unsuspected ability of BQR to inhibit tyrosine phosphorylation in lymphocytes.