Mechanism of Action of Mycophenolate Mofetil

Ransom, John

doi:10.1097/00007691-199512000-00023

Cited by 258 publications

(140 citation statements)

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“…In contrast, rapamycin (RAP) inhibits the ability of lymphocytes to proliferate in response to IL-2 by preventing the down-regulation of cell cycle inhibitors such as Kip-1 and thus blocks the transition from G1 into S phase [5]. Mycophenolic acid and methotrexate exert antiproliferative effects by interfering metabolically with DNA synthesis [6,7] and cyclophosphamide inhibits T cell proliferation by introducing DNA damage [8]. While ISD have been described to prevent the activation and expansion of resting T cells, it is not known whether they silence the action of activated T cells and turn them into a state of unresponsiveness (anergy) or whether they delete antigen-activated T cells and lead to long-lasting immunological tolerance.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

151

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SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.

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Section: Introductionmentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

151

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“…8 Of the several enzymes involved in guanylate biosynthesis, inositol monophosphate dehydrogenases 1 and 2 (IMPDH-1, -2), functional antagonists of GMPR (Figure 1a), have been targeted clinically with several drugs including the most specific one, mycophenolic acid (MPA) and its salt, mycophenolate mofetil (MMF). [10][11][12][13] Nonetheless, prior studies demonstrated that MPA possesses poor anti-tumor activity, 14,15 and it is primarily used as an immunosuppressing agent in organ transplantation. [10][11][12] GMP synthase (GMPS) is the other functional antagonist of GMPR.…”

mentioning

confidence: 99%

“…[10][11][12][13] Nonetheless, prior studies demonstrated that MPA possesses poor anti-tumor activity, 14,15 and it is primarily used as an immunosuppressing agent in organ transplantation. [10][11][12] GMP synthase (GMPS) is the other functional antagonist of GMPR. GMPS catalyzes the amination of xanitol monophosphate (XMP) to GMP to promote GTP synthesis ( Figure 1a).…”

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confidence: 99%

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

et al. 2015

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Malignant melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. Here, we report that guanosine monophosphate synthase (GMPS), an enzyme required for the de novo biosynthesis of GMP, has a major role in invasion and tumorigenicity of cells derived from either BRAF V600E or NRAS Q61R human metastatic melanomas. Moreover, GMPS levels are increased in metastatic human melanoma specimens compared with primary melanomas arguing that GMPS is an attractive candidate for anti-melanoma therapy. Accordingly, for the first time we demonstrate that angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopius efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice. Our data identify GMPS as a powerful driver of melanoma cell invasion and warrant further investigation of angustmycin A as a novel anti-melanoma agent.

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“…MMF exerts its immunosuppressive action via the inhibition of purine biosynthesis [3]. Azathioprine (AZA) also interferes with the purine synthesis [4].…”

Section: Introductionmentioning

confidence: 99%

“…Azathioprine (AZA) also interferes with the purine synthesis [4]. Mycophenolic acid (MPA) is the bioactive metabolite of MMF [3]. However, MMF has been shown to be more effective in improving kidney graft survival than AZA [l, 21.…”

Section: Introductionmentioning

confidence: 99%

Mycophenolic acid reduces renin-angiotensin-system activity in cultured mouse medullary thick ascending limb cells

Yang

Chang

2002

Transplant International

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Mycophenolate mofetil (MMF) is a promising immunosuppressive agent. The intra-renal reninangiotensin system (RAS) plays an important role in the regulation of intra-renal hemodynamics. Mycophenolic acid (MPA) is the bioactive metabolite of MMF. The interaction between MPA and intra-renal RAS is still unclear. We hypothesized that MPA might affect intra-renal RAS activity. We chose models of cultured mouse medullary thick ascending limb (mTAL) cells for the experiments, as the mTAL is one of the major sites of intra-renal RAS. We investigated the angiotensinconverting enzyme (ACE) activity by means of enzymatic assay, and the angiotensin-receptor activity by means of a binding study with radiolabeled angiotensin 11, and measured the intracellular calcium concentration in cultured cells treated with and without MPA. ACE activity changed neither in cells incubated with MPA nor in those treated without MPA. The binding study also indicated decreased angiotensin-I1 binding in MPA-treated (MPA lop7 M) cells, up to 43.7%. The decreased intracellular calcium concentration in MPA-treated cells further confirmed the MPA-inhibitory effect on the angiotensin receptor. We conclude that MPA reduces intra-renal RAS activity mainly through the decrease of AT1 receptor activity without affecting ACE activity. The results suggest that the inhibitory effect of MPA in the intra-renal RAS might play a role in the extra-immunosuppressive effect of MMF.

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Mechanism of Action of Mycophenolate Mofetil

Cited by 258 publications

References 0 publications

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

Mycophenolic acid reduces renin-angiotensin-system activity in cultured mouse medullary thick ascending limb cells

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