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The antilymphocytic activity of brequinar sodium and its potentiation by cytidine: Effects on lymphocyte proliferation and cytokine production

Woo, J and Lemster, B and Tamura, K and Starzl, TE and Thomson, AW (1993) The antilymphocytic activity of brequinar sodium and its potentiation by cytidine: Effects on lymphocyte proliferation and cytokine production. Transplantation, 56 (2). 374 - 381. ISSN 0041-1337

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Abstract

Based on its capacity to inhibit de novo pyrimidine biosynthesis by blocking dihydroorotate dehydrogenase activity, the antitumor agent brequinar sodium (BQR) has emerged as a new immunosuppressive agent. Since BQR is known to prevent the synthesis of nucleotides during cell proliferation, we hypothesized that it would be highly effective in controlling strong lymphocyte proliferative responses but might be less effective in controlling comparatively weak responses that do not necessarily involve new nucleotide synthesis. We addressed this question by culturing murine spleen cells with different types of stimuli, including Con A, phorbol myristate acetate ± ionomycin, anti-CD3, and anti-Igs. Addition of BQR (0.001 μg/ml to 10 μg/ml) at the start of a 72-hr culture period caused dose-dependent inhibition of strong proliferative responses, induced either by Con A (5 μg/ml) or PMA + ionomycin. A residual degree of proliferation persisted, however, even at the highest BQR concentrations. In contrast, no impairment of low-concentration Con A (0.5 or 0.1 μg/ml) anti-CD3, or anti-Igs responses was observed. In order to ascertain its role in arresting nucleotide synthesis, we attempted to reverse the inhibitory effect of BQR by adding exogenous uridine or cytidine to lymphocyte cultures. BQR's inhibitory activity was reversed completely by adding uridine at 0.1 mM. In contrast, combination of BQR and cytidine (0.1 mM) potentiated BQR's activity and abrogated anti-CD3 or anti-Igs-induced lymphocyte proliferation in a dose-dependent manner. A synergistic inhibitory action between BQR and cytidine was observed when the BQR concentration was higher than 0.1 μg/ml and with cytidine at 0.1 mM. Production of interleukin-2 and IL-4 was only slightly affected by BQR, but was significantly suppressed by coadministration of BQR and cytidine. Neither BQR (5 μg/ml) on its own, however, nor combination of BQR with cytidine affected production of mRNA for IL-2, IL-4, or interferon-Γ, as determined by reverse-transcription polymerase chain reaction. Our observations suggest that BQR may not only affect dihydroorotate dehydrogenase activity, but may also inhibit the enzyme cytidine deaminase, which converts cytidine to uridine. These antimetabolic effects of BQR complement the well-known cytokine synthesis inhibitory actions of FK506 or CsA. The combination of BQR and cytidine, however, offers a further possibility for inhibition of both cytokine production and T and B cell proliferation, and may have potential for the control of graft rejection. © 1993 by Williams & Wilkins.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Woo, J
Lemster, B
Tamura, K
Starzl, TEtes11@pitt.eduTES11
Thomson, AW
Centers: Other Centers, Institutes, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 1993
Date Type: Publication
Journal or Publication Title: Transplantation
Volume: 56
Number: 2
Page Range: 374 - 381
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 0041-1337
Other ID: uls-drl:31735062112762, Starzl CV No. 1483
Date Deposited: 08 Apr 2010 17:25
Last Modified: 04 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/4869

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