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PubMed1993

Brequinar sodium inhibits interleukin-6-induced differentiation of a human B-cell line into IgM-secreting plasma cells.

Brequinar sodium (BQR) has been shown recently to be a potent immunosuppressive agent. This property has been attributed to the capacity of BQR to inhibit de novo pyrimidine nucleoside biosynthesis and consequently, to blockade the synthesis both of DNA and RNA. The influence of this new immunosuppressant on lymphocyte function has not been fully characterized. To determine the potential efficacy of BQR for the control of antibody-mediated graft rejection, which is of particular significance in the context of xenotransplantation, we have examined the influence of the drug on interleukin-6-dependent IgM production by the human B-cell line, SKW 6.4. At concentrations up to 10 micrograms/ml, BQR did not affect concanavalin A (Con A)-induced human peripheral blood lymphocyte proliferation or IL-6 production by blood mononuclear leucocytes. In contrast, the drug was very effective in inhibiting IL-6-stimulated IgM production by SKW 6.4 cells, with an optimal inhibitory concentration of 0.3 microgram/ml. As expected, addition of exogenous uridine (0.1 mM), the precursor of uridine triphosphate (UTP), reversed the inhibitory effect of BQR on antibody production, while cytidine (0.1 mM) potentiated the inhibitory activity of the drug. It was further demonstrated that the inhibition of IgM production was unrelated to DNA synthesis, indicating that BQR may affect IL-6 signal transduction and IgM production in SKW 6.4 cells independent of any effect on cell proliferation.

B-Lymphocytes↗
PubMed1993

Prevention of vascularized allograft and xenograft rejection in rodents by brequinar sodium.

The data that has been obtained from preclinical studies in rodents demonstrate that BQR is an effective primary immunosuppressive agent with important advantages for use in transplantation immunotherapy. The drug is highly effective when used as a single agent to prevent the rejection of a variety of vascularized allografts and xenografts. BQR is easily administered orally, the drug displays a high level of bioavailability, and drug plasma levels and immunosuppressive activity can be directly measured. The adverse side effects seen with the drug are those normally associated with antiproliferative drugs and are predictable and easily reversed by treatment withdrawal. Most importantly, perhaps, is the broad range of synergistic activity when used in combination with new immunosuppressive drugs. We believe that the combination of these attributes separate BQR from many of the new drugs now under study. Some, for example, do not exhibit synergism (CsA and FK 506), others have may have problems with inadequate oral bioavailability (MPM and rapamycin), and some exhibit the potential for substantial toxicity (15-DSG, myzorbine). The data derived from the use of BQR in combination with other immunosuppressive drugs, such as the studies described above, are important. They provide direct evidence to support the concept that the next important advances in immunosuppressive therapy will involve the use of an effective multidrug approach to preventing organ graft rejection. Combination therapies with immunosuppressive drugs that exhibit different modes of action improve graft survival, widen therapeutic windows, and reduce the risk of toxic side effects. The experimental evidence that several of these combinations are potentially useful is solid, consistent, and exciting. It is our expectation from the rodent experiments described in this symposium that the treatment of allograft (and perhaps xenograft) rejection will consist of the use of CsA (or FK 506), BQR, and a third drug such as rapamycin or mycophenolate mofetil, the choice of which will be heavily influenced by the development of either analogues of these drugs or perhaps new compounds with improved bioavailability and effective monitoring techniques.

Animals↗
PubMed1993

Brequinar sodium: monitoring immunosuppressive activity.

There has been remarkable consistency in our laboratory for the experimental results derived from a variety of allogeneic and xenogeneic models of organ transplantation using BQR, a primary immunosuppressive agent, to prevent graft rejection. Considerable knowledge exists in a number of species with respect to the dose-response immunosuppressive efficacy, organ specificity, peripheral drug measurements, toxic side-effects, species sensitivity, and synergistic drug interactions. Despite the complexity of transferring experimental results to the clinical setting, the cumulative experience with this new immunosuppressive compound suggests that it may be highly effective when used for clinical transplantation. The identification of a predictive monitoring technique(s) would provide clinicians with a highly sensitive marker to effectively regulate BQR posttransplantation immunosuppressive therapies. Although the maintenance of a "therapeutic window" of immunosuppressive efficacy did not necessarily prevent the rejection of allografts or xenografts in the rat models tested, there was an important correlation between elevated BQR levels and the onset of recipient toxicity. Increased morbidity and mortality was noted when BQR blood levels were elevated above 16 micrograms/mL. The measurement of pyrimidine biosynthetic pathway metabolites provided a direct correlation between graft viability, global depletion of nucleotides (UTP, CTP, ATP, GTP), and suppression of PHA-mitogenic lymphocyte proliferative responses when different doses of BQR were tested. The analysis of these parameters were less informative following combination therapy with CsA. As with other immunosuppressive agents, the difficulty in relying exclusively on plasma trough drug levels as an accurate means to project graft viability may be influenced by individual differences in absorption, metabolism, and excretion of the compound. Additional parameters that may provide valuable information for the posttransplant therapeutic course include drug bioavailability, peak levels, drug clearance, or inhibition of immune response. It is anticipated that these studies will provide important baseline information for further refinement of these monitoring techniques to aid in posttransplant patient management.

Animals↗