Disease relevance of mizoribine

• Bredinin caused marked chromosomal aberrations such as breakages, translocations, and fragmentation in L5178Y cells [1].
• These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas [2].
• Both sublines of L1210 and P388 leukemia resistant to neplanocin A were cross-resistant in vitro to bredinin and 9-beta-D-arabinofuranosyladenine, which have been reported to be activated by adenosine kinase [3].
• A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome [4].
• Monitoring serum concentrations of mizoribine is imperative to determine toxic (enteritis) levels [5].

High impact information on mizoribine

• To further characterize the mechanism of action of this drug, we studied the effect of mizoribine on human peripheral blood T cells stimulated with alloantigen, anti-CD3 MAb, or pharmacologic mitogens [6].
• Based on studies in cell lines, mizoribine has been postulated to be an inhibitor of inosine monophosphate (IMP) dehydrogenase (EC1.2.1.14), a pivotal enzyme in the formation of guanine ribonucleotides from IMP [6].
• Measurements of purine ribonucleotide pools by HPLC showed that mizoribine led to a decrease in intracellular GTP levels, and that repletion of GTP reversed its antiproliferative effects [6].
• Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine [6].
• Inhibition by bredinin at a low GMP; but at higher concentrations of bredinin the inhibition was not reversed even when the concentration of GMP was raised [1].

Chemical compound and disease context of mizoribine

• Body weights, blood cell counts, serum chemistry profiles, serum electrolyte levels, urinalysis with cytology and culture, lymphocyte stimulation assays, immunoglobulin levels, whole blood levels of cyclosporine, and serum levels of mizoribine were followed [5].
• Furthermore, we investigated the effect of mizoribine, an immunosuppressive agent, on the interstitial fibrosis induced by UUO, demonstrating that mizoribine, but not prednisolone, significantly improves the tubulointerstitial fibrosis by suppressing the macrophage infiltration and the expression of alpha-smooth muscle actin [7].
• BACKGROUND: We investigated the efficacy of oral mizoribine pulse therapy (mizoribine-pulse) for cyclosporin (CyA)-dependent, steroid-resistant nephrotic syndrome (SRNS) and frequently relapsing, steroid-dependent nephrotic syndrome (FR-SDNS) [8].
• Steroid-sparing effect of mizoribine in long-term nephrotic syndrome of children [9].
• The present study was made to investigate the antinephritic effect of mizoribine in comparison to that of azathioprine by using the nephrotic type of anti-rat glomerular basement membrane rabbit serum (anti-GBM serum)-induced nephritis in rats [10].

Biological context of mizoribine

• Cell cycle analysis disclosed that mizoribine significantly decreased the numbers of B cells in S + G2 + M phases [11].
• Moreover, the data demonstrate that mizoribine interferes with the cell cycle progression of activated B cells by suppressing the expression of cyclin A by a mechanism distinct from guanine ribonucleotide depletion [11].
• Based on the amino acid sequence analysis of these proteins, 60- and 43-kDa mizoribine-binding proteins were identified with HSP60 and cytosolic actin, respectively [12].
• Incubation of human CEM leukemia cells for 2 hr with IC50 concentrations of either mizoribine (4 microM) or mycophenolic acid (0.5 microM) reduced cellular GTP levels an average of 68% or 58%, respectively, compared with the levels in control cells [13].
• Mizoribine pharmacokinetics and pharmacodynamics in a canine renal allograft model of local immunosuppression [14].

Anatomical context of mizoribine

• These results indicate that mizoribine directly suppresses the function of human B cells without interfering with the initial phase of activation [11].
• We investigated their specific binding proteins using mizoribine affinity column chromatography and porcine kidney cytosols [12].
• The IMP dehydrogenase inhibitors, bredinin and mycophenolic acid (MA), induced, in a dose-dependent manner, the resumption of maturation in cumulus cell-enclosed oocytes maintained in meiotic arrest by hypoxanthine but had no effect on denuded oocytes [15].
• Mizoribine improves renal tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-treated rat by inhibiting the infiltration of macrophages and the expression of alpha-smooth muscle actin [7].
• These findings suggest mizoribine could induce differentiation in HL-60 and U937 cells through a decrease of intracellular GTP levels [16].

Associations of mizoribine with other chemical compounds

• On different types of mizoribine affinity columns, HSP60 or actin recognized the NH(2) group of mizoribine, and this group may be a functional group of the agent [12].
• Combination effect of mycophenolate mofetil with mizoribine on cell proliferation assays and in a mouse heart transplantation model [17].
• All 107 patients were treated with cyclosporine or tacrolimus based immunosuppression, including methylprednisolone and azathioprine or mizoribine [18].
• Using this replicon cell culture system, it was demonstrated further that neither ribavirin nor its derivative mizoribine accelerated the mutation rate or the increase in the genetic diversity of HCV replicon [19].
• The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells [20].

Gene context of mizoribine

• Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages [21].
• Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine [11].
• Although mizoribine did not suppress the expression of CD25 and cdc2 kinase, mizoribine markedly suppressed the expression of cyclin A in SA-activated B cells [11].
• Although at pharmacologically attainable concentrations both mizoribine and methotrexate suppressed the production of IgM of SAC-activated B cells, mizoribine, but not methotrexate, decreased the expression of cyclin A protein as well as mRNA in B cells stimulated with SAC + IL-2 [22].
• These results indicated that HSP60 has high affinity to mizoribine, and the interaction was also observed on surface plasmon resonance analysis [12].

Analytical, diagnostic and therapeutic context of mizoribine

• The immunosuppressive drug, mizoribine, has been used to prevent rejection of organ allografts in humans and in animal models [6].
• Likewise, the MPA-resistant strain was more sensitive to mizoribine in cell culture [23].
• Mizoribine has been used to prevent rejection of organ allografts in humans and in animal models [11].
• Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation [24].
• Oral administration of cyclosporine did not exacerbate mizoribine enterotoxicity in the dog when administered with mizoribine at a dose that produced histopathologic signs of enterotoxicity [25].

References