Showing papers on "Prinomastat published in 2003"
TL;DR: It is hoped that as the understanding of the complex process of angiogenesis increases, so will the ability to design more effective targeted therapies as well as early enthusiasm for many of these agents.
102 citations
TL;DR: The results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism, and EMMPRIN may play an important role in the release and activation of MMPs during lung injury.
Abstract: High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.
101 citations
TL;DR: It is hoped that as the understanding of the complex process of angiogenesis increases, so will the ability to design more effective targeted therapies.
48 citations
TL;DR: It is concluded that combined treatment with 15 mg prinomastat plus chemotherapy approximately doubles the hazard of VTE among patients with advanced NSCLC.
Abstract: Two clinical trials have suggested that the combination of vascular endothelial growth factor inhibitor with chemotherapy is associated with venous thromboembolism (VTE). This retrospective cohort study investigates whether a similar association exists when matrix metalloproteinase inhibitor (prinomastat) is combined with chemotherapy. Patients (n=1,023) with stage IIIB, IV, or recurrent non-small cell lung cancer (NSCLC) were followed during 2 randomized, double-blind trials of prinomastat versus placebo orally bid, plus gemcitabine/cisplatin (GC) or paclitaxel/carboplatin (PC). VTE included deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed by imaging or autopsy. Risks identified in univariate analysis (incidence densities compared by t test) were confirmed in multivariate analysis (proportional hazards model). During 7,500.3 patient-months, 58 VTE (31 PE, 27 isolated DVT) were confirmed in 54 patients. On univariate analysis, VTE was associated with central venous catheter placed within 3 months, 15 mg prinomastat plus GC, and to a lesser extent, 15 mg prinomastat plus PC, baseline performance status, and histologic type. VTE incidence was not increased by 15 mg prinomastat alone (post-discontinuation of chemotherapy), by chemotherapy plus placebo, or by 5 or 10 mg prinomastat plus chemotherapy. On multivariate analysis,VTE hazards (95% confidence interval) were 5.69 (2.61, 12.40) with recently placed central catheter, 2.78 (1.42, 5.43) with 15 mg prinomastat plus GC, and 2.06 (0.98, 4.31) with 15 mg prinomastat plus PC; performance status and histology were nonsignificant. We can conclude that combined treatment with 15 mg prinomastat plus chemotherapy approximately doubles the hazard of VTE among patients with advanced NSCLC.
39 citations
TL;DR: The results suggest that the administration of prinomastat in combination with standard cytotoxic chemotherapy during early stages of tumor growth and metastasis may prolong survival in non-small cell lung cancer (NSCLC) patients.
25 citations
TL;DR: The studies suggest that MT1‐MMP could actually promote cell migration via modification of the cell surface receptors, including αvβ3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins.
Abstract: Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have demonstrated that in the case of breast carcinoma MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin, the proteinase processes the pro-alphav integrin subunit, thus facilitating alphavbeta3 integrin maturation and cell migration on vitronectin. Our findings show that cell surface MT1-MMP is a short-lived protein with a life span in the range of several hours. In contrast, turnover of alphavbeta3 integrin is much slower. The half-life of alphavbeta3 heterodimer is about 24 hr. This large difference in life span allowed us to distinguish between the effects of MT1-MMP on cell migration brought by matrix proteolysis from those imposed through alphavbeta3 integrin maturation. We then modulated the enzyme's activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze the divergent effects of MT1-MMP on cell migration. Although Prinomastat immediately blocked MT1-MMP-mediated matrix degradation, the pool of MT1-MMP-modified alphavbeta3 integrin molecules was still capable of mediating cell-matrix interactions. To our considerable surprise, inhibition of MT1-MMP-dependent vitronectin proteolysis by Prinomastat allowed a several-fold increase in migration of MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin. In contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell motility. Our studies suggest that MT1-MMP could actually promote cell migration via modification of the cell surface receptors, including alphavbeta3 integrin, rather than facilitate cell migration through direct cleavage of the matrix proteins.
25 citations
Patent•
24 Dec 2003
TL;DR: In this paper, the MMPI is defined as a Tissue Inhibitor of Matrix Metalloproteinas (e.g., TIMP-1, TIMM-2, TIMMP-3 or TIMP/TIMP-4).
Abstract: Compositions and devices including collagen and a metalloprotease inhibitor, and methods of making and using same. The compositions may further include hydroxyapatite. Within certain embodiments the MMPI is a Tissue Inhibitor of Matrix Metalloproteinas (e.g.,.TIMP-1, TIMP-2, TIMP-3 or TIMP-4). Within other embodiments, the MMPI is tetracycline, or an analog or derivative thereof (e.g., minocycline, or doxycline); a hydroxamate (e.g., BATIMISTAT, MARIMISTAT, or, TROCADE); RO-1130830, CGS 27023A, BMS-275291, CMT-3, SOLIMASTAT, ILOMASTAT, CP-544439, PRINOMASTAT, PNU-1427690, or SU-5402. In other aspects, the MMPI may be a polypeptide inhibitor (e.g., an inhibitor of a matalloprotease maturase), a mercapto-based compound, or a bisphosphanate.
2 citations
Patent•
10 Jun 2003
TL;DR: In this article, a matrix metalloproteinase inhibitor prinomastat and their synthesis were discussed. But the synthesis of the matrix metallo-pyridin-4yloxy-(1-oxypyridepyridis-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid amide was not discussed.
Abstract: Metabolites of a matrix metalloproteinase inhibitor prinomastat and their synthesis. These metabolites are: (3S)-N-hydroxy-4-(4-((1-oxy-pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (M6); (3S)-2,2-dimethyl-1,1-dioxo-4-[4-(1-oxy-pyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid amide (M7); (3S)-2,2-dimethyl-4-[4-(1-oxypyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid amide (M8); (3S)-2,2-dimethyl-1,1-dioxo-4-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylic acid amide (M2); and (3S)-2,2-dimethyl-4-[4-(pyridin-4yloxy)-benzenesulfonyl)-thiomorphpline-3-carboxylic acid amide (M3).
1 citations