Pyrimidine-2,4,6-Triones: A New Effective and Selective Class of Matrix Metalloproteinase Inhibitors

Grams, Frank; Brandstetter, Hans; D’Alò, S.; Geppert, D.; Hw, Krell; Leinert, Herbert; Lívi,; Menta, Ernesto; Oliva, Ambrogio; Zimmermann, Gerd; Gram, F; E, Livi VMenta

doi:10.1515/bc.2001.159

Cited by 128 publications

(100 citation statements)

References 18 publications

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“…Addition of GM6001 representing a broad-spectrum inhibitor of MMP activity significantly reduced the transmigration rate of hMSCs (Figure 2). Ro 206-0222, a highly specific inhibitor of MMP-2, MMP-9, and MT1-MMP activity, 41 impaired the invasive capacity of hMSCs to a similar extent (Figure 2). Cell viability was not affected by either of the 2 inhibitors at the concentration used to achieve maximal migratory inhibition (data not shown).…”

Section: Hmscs Are Able To Traverse Human Ecm: Blockage By Mmp Inhibimentioning

confidence: 80%

“…For migratory inhibition experiments hMSCs were preincubated for 30 minutes with 10 g/mL GM6001 (Calbiochem), a synthetic broadspectrum MMP inhibitor, 40 or with the same concentration of Ro 206-0222, a highly specific inhibitor for MMP-2, MMP-9, and MT1-MMP 41 (kindly provided by Dr Krell, Roche Diagnostics, Pharma Research Penzberg, Germany), before being transferred into the upper compartment. The respective inhibitors were also added to the medium in the upper and lower compartments in the same concentrations.…”

Section: Cell Invasion Assaymentioning

confidence: 99%

“…hMSCs were placed onto Transwell filters coated with human ECM and incubated for 48 hours in the absence (control) or presence of the broad-spectrum MMP inhibitor GM6001 (10 g/mL) or Ro 206-0222 (10 g/mL), a highly specific inhibitor of MMP-2, MMP-9, and MT1-MMP. 41 Cell invasion rate was determined in the percentage relative to control (set as 100%). Data are presented as mean Ϯ SD of 1 triplicate experiment representative of 3 independent experiments.…”

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confidence: 99%

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MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Ries

Egea

Karow

et al. 2007

Blood

477

384

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IntroductionHuman mesenchymal stem cells (hMSCs) from bone marrow are characterized by their ability of self-renewal paired with the capacity to differentiate into diverse mesodermal cell types such as osteoblasts, chondrocytes, and adipocytes. 1,2 Moreover, hMSCs were shown to give rise to cells beyond the germ layers with visceral mesoderm, neuroectoderm, or endoderm characteristics. [2][3][4] Additional functions have been reported for hMSCs in providing cytokine and growth factor support for the expansion of hematopoetic 5 and embryonic stem cells, 6 or by playing an immunomodulatory role. 7 One of the most remarkable but least understood findings is the ability of hMSCs to migrate from bone marrow or peripheral blood into damaged tissues. Transplantation experiments in animals and patients demonstrated that mesenchymal stem cells migrate to sites of injury, where they enhance wound healing, 8 support tissue regeneration following myocardial infarction, 9 home to and promote the restoration of bone marrow microenvironment after damage by myeloablative chemotherapy, 10 or help to overcome the molecular defect in children with osteogenesis imperfecta. 11 Another interesting observation is that systemically delivered hMSCs are mobilized to and integrate into tumor tissue. 12 Taken together, these exciting features have rendered hMSCs a promising tool for tissue engineering 13 as well as multiple cell and gene therapy strategies. [14][15][16] Detailed studies have demonstrated that homing of hematopoetic stem cells from blood into bone marrow or their mobilization from bone marrow into blood and tissues is mainly controlled by cytokines/chemokines, adhesion molecules, and proteolytic enzymes. [17][18][19] However, little is known about the molecular mechanisms regulating cell movement and relocalization in hMSCs.A key requirement for cells to reach distant target sites is the ability to traverse the protein fibers of the extracellular matrix (ECM) which is present between cells of all tissue types. 20 Basement membranes represent a specialized form of the ECM that separate epithelium or endothelium from stroma by a dense layer of ECM. To overcome these matrix barriers, migrating cells require specific proteolytic enzymes. Besides some serine-and cysteineproteinases, in particular the matrix metalloproteinases (MMPs) consisting of more than 24 zinc-dependent endopeptidases, are capable of degrading ECM components. Consequently, MMPs are found to be involved in various physiologic and pathologic processes. 21 The 2 gelatinases, MMP-2 and MMP-9, preferentially cleave denatured collagens (gelatin), laminin, and collagen type IV as the major constituent of basement membranes. 20,21 Biosynthesis and activity of the gelatinases are associated with the invasive capacity of various cell types such as leukocytes, endothelial cells, and metastasizing tumor cells. 22-24 MMP-2 and MMP-9 are secreted from the cells as latent zymogens which are rapidly complexed by their specific endogenous inhibitors, the tissue inhibitor of ...

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Section: Hmscs Are Able To Traverse Human Ecm: Blockage By Mmp Inhibimentioning

confidence: 80%

Section: Cell Invasion Assaymentioning

confidence: 99%

mentioning

confidence: 99%

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MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Ries

Egea

Karow

et al. 2007

Blood

477

384

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“…The greatest progress has been made when inhibitors were synthesized which were relatively specific for gelatinases (22) or even displayed mechanism-based binding to gelatinases (23,24). Indeed, these gelatinase-specific inhibitors were efficient in inhibiting aggressive metastasis in the well-established syngeneic and immunocompetent L-CI.5s lymphoma liver metastasis model (25,26).…”

Section: Introductionmentioning

confidence: 99%

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg

Kopitz²,

Schaten³

et al. 2008

Molecular Cancer Research

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The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell -derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell -derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341 -51)

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“…1) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) (Grams et al, 2001;Lein et al, 2002;Mangoldt et al, 2002;Noel et al, 2000;Opalka et al, 2002). These enzymes have recently become important in the field of anticancer drug research: they play a crucial and complex role in tumor growth, angiogenesis and formation of metastasis (Egeblad and Werb, 2002;Fingleton, 2003;Overall and Lopez-Otin, 2002;Vihinen and Kahari, 2002).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions

Piette

Évrard

Frankenne

et al. 2006

European Journal of Pharmaceutical Sciences

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Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-β-cyclodextrin (HP-β-CD) and L-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p < 0.05) increase in absolute bioavailability. The area undercurve (AUC) and the peak serum concentration (C max ) were approximately 10 times higher than those obtained with the suspension, while the time (T max ) to reach C max was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5 h) and a small overall volume of distribution (81).

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Pyrimidine-2,4,6-Triones: A New Effective and Selective Class of Matrix Metalloproteinase Inhibitors

Cited by 128 publications

References 18 publications

MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions

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