Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

Hande, Kenneth R.; Collier, Mary; Paradiso, Linda J.; Stuart-Smith, Jill; Dixon, Mary; Clendeninn, Neil J.; Yeun, Geoff; Alberti, D.; Binger, Kimberly; Wilding, George

doi:10.1158/1078-0432.ccr-0981-3

Cited by 41 publications

(32 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although MMP inhibitors have yet to be tested in STS, several have been evaluated as antiangiogenic or antimetastatic agents in clinical trials for advanced pancreatic, gastric, prostate, and lung cancer (29)(30)(31)(32). Collectively, the results of these trials have been disappointing with no apparent efficacy but increased concomitant morbidity.…”

Section: Discussionmentioning

confidence: 99%

Wild-type p53 Inhibits Nuclear Factor-κB–Induced Matrix Metalloproteinase-9 Promoter Activation: Implications for Soft Tissue Sarcoma Growth and Metastasis

Liu

Zhan

Hannay

et al. 2006

Molecular Cancer Research

View full text Add to dashboard Cite

Human soft tissue sarcoma (STS) is a highly lethal malignancy in which control of metastasis determines survival. Little is known about the molecular determinants of STS dissemination. Here, we show that human STS express high levels of matrix metalloproteinase-9 (MMP-9) and that MMP-9 expression levels correlate with sequence analysisdefined p53 mutational status. Reintroduction of wild-type p53 (wtp53) into mutant p53 STS cell lines decreased MMP-9 mRNA and protein levels, decreased zymography-assessed MMP-9 proteolytic activity, and decreased tumor cell invasiveness. Reintroduction of wtp53 into STS xenografts decreased tumor growth and MMP-9 protein expression. Luciferase reporter studies showed that reintroduction of wtp53 into mutant p53 STS cells decreased MMP-9 promoter activity. Deletion constructs of the MMP-9 promoter identified a region containing a p53-responsive element that lacked a p53 consensus binding site but did contain a nuclear factor-KB (NF-KB) site. Mutating this NF-KB binding site eliminated the wtp53-repressive effect. Electrophoretic mobility shift assays confirmed decreased NF-KB binding in STS cells in the presence of wtp53. Our findings suggest a role for MMP-9 in STS progression and expand the role of p53 in molecular control of STS growth and metastasis. Therapeutic interventions in human STS targeting MMP-9 activity directly or via reintroduction of wtp53 merit further investigation. (Mol Cancer Res 2006;4(11):803 -10)

show abstract

Section: Discussionmentioning

confidence: 99%

Wild-type p53 Inhibits Nuclear Factor-κB–Induced Matrix Metalloproteinase-9 Promoter Activation: Implications for Soft Tissue Sarcoma Growth and Metastasis

Liu

Zhan

Hannay

et al. 2006

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Numerous proteases were identified, and of interest were several matrix metalloproteases (MMP), due to recent evidence that prion protein fragments can be digested by membrane-type MMP proteases [62]. To investigate the possibility of MMP mediated c-cleavage of PrP C , we treated MycRK cells for 24 h with the MMP inhibitor Prinomastat, which is selective for MMPs-2, 3, 9, 13 and 14 [63]. We observed a significant decrease in relative C3 levels for all concentrations of Prinomastat tested (Fig.…”

Section: Prpmentioning

confidence: 99%

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Lewis

Johanssen

Crouch

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The cellular prion protein (PrP C ) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrP C is recognized to undergo both a-and b-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrP C , as well as the selective use of a far-Cterminal anti-PrP antibody, we have identified a new PrP C fragment, nominally 'C3', and elaborating existing nomenclature, 'c-cleavage' as the responsible proteolysis. Our studies indicate that this novel c-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrP C has reached the cell surface, by a matrix metalloprotease.We found that C3 is GPI-anchored like other C-terminal and full length PrP C species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, c-cleavage may increase in human prion diseases. Given the likely relevance of PrP C processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration.

show abstract

“…AG3340 inhibits MT1-MMP with a K i in a sub-nanomolar range. AG3340 was used in cancer Phase I-III clinical trials (22). To evaluate AG3340, we used both IS-CD8 ϩ cells and the splenocytes isolated from newly diabetic NOD mice (12).…”

Section: Inhibition Of Mt1-mmp Represses the Diabetogenicity Of Is-cd8mentioning

confidence: 99%

Inhibition of Membrane Type-1 Matrix Metalloproteinase by Cancer Drugs Interferes with the Homing of Diabetogenic T Cells into the Pancreas

Savinov

Rozanov

Golubkov

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase (MT1-MMP) and the onset of disease in a rodent model of type 1 diabetes in non-obese diabetic mice. We determined that MT1-MMP proteolysis of the T cell surface CD44 adhesion receptor affects the homing of T cells into the pancreas. We also determined that both the induction of the intrinsic T cell MT1-MMP activity and the shedding of cellular CD44 follow the adhesion of insulin-specific, CD8-positive, K d -restricted T cells to the matrix. Conversely, inhibition of these events by AG3340 (a potent hydroxamate inhibitor that was widely used in clinical trials in cancer patents) impedes the transmigration of diabetogenic T cells into the pancreas and protects non-obese diabetic mice from diabetes onset. Overall, our studies have divulged a previously unknown function of MT1-MMP and identified a promising novel drug target in type I diabetes. Insulin-dependent diabetes mellitus (IDDM)1 (type I diabetes) is a T cell-mediated, autoimmune disease. The pathogenesis of IDDM involves the activation of autoimmune T cells followed by their homing into the pancreatic islets (1). In the islets, T cells destroy insulin-producing ␤ cells (2). The CD44 surface receptor is elevated in activated T cells and, via its interactions with endothelial hyaluronan, contributes to T cell adhesion on the endothelium and the subsequent transmigration events (3). MT1-MMP, a multifunctional membrane-tethered enzyme, functions in cancer cells as one of the main mediators of pericellular proteolytic events and directly cleaves cell receptors (4, 5). CD44, a major hyaluronan receptor, is a well-established target of MT1-MMP in tumor cells (6 -9). MT1-MMP cleavage releases the extracellular domain of CD44 from the cell surfaces and inactivates the functionality of the CD44 adhesion receptor. Evidence suggests that MT1-MMP proteolysis of CD44 significantly affects the adhesion and migration of malignant cells (6, 9, 10).Consistently, we hypothesized that MT1-MMP also targets CD44 in T cells and that these proteolytic events regulate transmigration of the diabetogenic T cells into the pancreatic islets. In agreement with our hypothesis, we have determined here that pharmacological inhibition of T cell MT1-MMP enhances adhesion of the diabetogenic T cells to the pancreatic endothelium. Conversely, the enhanced adhesion of T cells significantly diminishes their subsequent homing into the pancreatic islets. Our results also imply that the inhibition of T cell MT1-MMP is key to the delay of the onset of diabetes in non-obese diabetic (NOD) mice, a well-accepted rodent model of IDDM. EXPERIMENTAL PROCEDURESMice and Cells-NOD mice of NOD/LtJ strain were obtained from the Jackson Laboratory. IS-CD8 ϩ T cells (insulin-specific, CD8-positive, K d -restricted T cells of the TGNFC8 clone from the pancreas of NOD mouse) (11) were maintained in Click's medium supplemented with 5% fetal calf ser...

show abstract

Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

Cited by 41 publications

References 22 publications

Wild-type p53 Inhibits Nuclear Factor-κB–Induced Matrix Metalloproteinase-9 Promoter Activation: Implications for Soft Tissue Sarcoma Growth and Metastasis

Wild-type p53 Inhibits Nuclear Factor-κB–Induced Matrix Metalloproteinase-9 Promoter Activation: Implications for Soft Tissue Sarcoma Growth and Metastasis

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Inhibition of Membrane Type-1 Matrix Metalloproteinase by Cancer Drugs Interferes with the Homing of Diabetogenic T Cells into the Pancreas

Contact Info

Product

Resources

About