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Expert Opinion on Investigational Drugs Sep 2000Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar... (Review)
Review
Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar selectivity should represent an advantage for prinomastat in terms of efficacy/tolerability. The drug has been shown to inhibit tumour growth and angiogenesis in a variety of preclinical models, including cancer of colon, breast, lung and intriguingly in melanoma and glioma models. Moreover, the combination of prinomastat and several chemotherapeutic agents was shown to induce additive effects. The drug is currently in Phase III clinical trials for patients with non-small cell lung cancer in combination with paclitaxel and carboplatin, as well as in advanced hormone refractory prostate cancer in combination with mitoxantrone. The most common side effects are musculoskeletal pain and stiffness. These side effects generally cease with treatment interruption. Finally, considering the pathophysiology of MMPs, Agouron is exploring the utility of prinomastat in ophthalmology and dermatology.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Glioblastoma; Humans; Macular Degeneration; Metalloendopeptidases; Neovascularization, Pathologic; Organic Chemicals
PubMed: 11060800
DOI: 10.1517/13543784.9.9.2159 -
Computers in Biology and Medicine May 2023The purpose of this study was using bioinformatics tools to identify biomarkers and molecular factors involved in the diagnosis of colorectal cancer, which are effective...
BACKGROUND
The purpose of this study was using bioinformatics tools to identify biomarkers and molecular factors involved in the diagnosis of colorectal cancer, which are effective for the diagnosis and treatment of the disease.
METHODS
We determined differentially expressed genes (DEGs) related to colorectal cancer (CRC) using the data series retrieved from GEO database. Then the weighted gene co-expression network analysis (WGCNA) was conducted to explore co-expression modules related to CRC diagnosis. Next, the relationship between the integrated modules with clinical features such as the stage of CRC was evaluated. Other downstream analyses were performed on selected module genes.
RESULTS
In this study, after performing the WGCNA method, a module named blue module which was more significantly associated with the CRC stage was selected for further evaluation. Afterward, the Protein-protein interaction network through sting software for 154 genes of the blue module was constructed and eight hub genes were identified through the evaluation of constructed network with Cytoscape. Among these eight hub genes, upregulation of MMP9, SERPINH1, COL1A2, COL5A2, COL1A1, SPARC, and COL5A1 in CRC was validated in other microarray and TCGA data. Based on the results of the mRNA-miRNA interaction network, SERPINH1 was found as a target gene of miR-940. Finally, results of the DGIDB database indicated that Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, and Bevacizumab, could be used as a therapeutic agent for targeting the MMP9. Furthermore, Ocriplasmin and Collagenase clostridium histolyticum could target COL1A1, COL1A2, COL5A1, and COL5A2.
CONCLUSION
Taken together, the results of the current study indicated that seven hub genes including COL1A2, COL5A1, COL5A2, SERPINH1, MMP9, SPARC, and COL1A1 which were upregulated in CRC could be used as a diagnostic and progression biomarker of CRC. On the other hand, miR-940 which targets SERPINH1 could be used as a potential biomarker of CRC. More ever, Andecaliximab, Carboxylated glucosamine, Marimastat, Tozuleristide, S-3304, Incyclinide, Curcumin, Prinomastat, Demethylwedelolactone, Bevacizumab, Ocriplasmin , and Collagenase clostridium histolyticum were introduced as therapeutic agents for CRC which their therapeutic potential should be evaluated experimentally.
Topics: Humans; Matrix Metalloproteinase 9; Bevacizumab; Curcumin; Microbial Collagenase; MicroRNAs; Biomarkers; Colorectal Neoplasms; Gene Regulatory Networks
PubMed: 36931200
DOI: 10.1016/j.compbiomed.2023.106779 -
International Journal of Cancer May 2003Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have been directly implicated in tumor cell dissemination and metastasis. We have...
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.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Enzyme Inhibitors; Humans; Integrin alphaVbeta3; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Organic Chemicals; Tumor Cells, Cultured; Vitronectin
PubMed: 12594807
DOI: 10.1002/ijc.10977 -
Journal of Ocular Pharmacology and... Jun 2001To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of...
To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of New Zealand White rabbits received intravitreous and subtenon injections of prinomastat or of acidified water vehicle as control, Doses of 0.5 mg in 0.05 mL of prinomastat or acidified water were used for intravitreal injection. For the subtenon injections, doses of 5 mg prinomastat in 0.5 mL of acidified water were administered in the superotemporal quadrant. Intraocular pharmacokinetics were determined by analyzing vitreous samples at different postinjection time points using Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LC-MS/MS). The toxicity was evaluated by biomicroscopy, electroretinography (ERG), pneumatonometry, and histology. No toxicity was found with either administration method. At day 14 after intravitreal injection, levels of prinomastat in the vitreous and choroid were 1.4 ng/mg and 7.8 ng/mg, respectively. The retinal levels of prinomastat were 22 ng/mg at 24 hr and dropped below 1 ng/mg at 48 hr. Prinomastat remained well above minimum effective concentration in the choroid for at least four weeks after a single intravitreal injection, suggesting that local intravitreal injection may have potential in treating choroidal neovascularization.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Chromatography, High Pressure Liquid; Drug Evaluation, Preclinical; Electroretinography; Gas Chromatography-Mass Spectrometry; Intraocular Pressure; Metalloendopeptidases; Organic Chemicals; Rabbits; Retina; Tonometry, Ocular; Vitreous Body
PubMed: 11436949
DOI: 10.1089/108076801750295326 -
Current Eye Research Feb 2002We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma...
PURPOSE
We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma model.
METHODS
Uveal melanoma xenograft was implanted to suprachoroidal space in each eye of 24 pigmented rabbits which were immunosuppressed with cyclosporine. One week after surgery, the eyes were randomized to receive prinomastat or the vehicle of the prinomastat intravitreally every week for 4 weeks. The take rate of the xenograft, tumor height, apoptosis, and necrosis in the eyes which developed tumors from the treatment and control groups were compared.
RESULTS
A tumor mass was identified in 8 of 24 (33%) prinomastat-treated eyes and 20 of 24 (83%) of the vehicle-treated eyes. Echographic measurements revealed a mean tumor height of 2.2 mm in the prinomastat-treated group and 3.8 mm in the control group in those eyes with take of tumor (p < 0.001). Stereomicroscopic measurements showed a mean tumor height of 1.9 mm in the treatment group and 3.9 mm in the control group (p < 0.001). The mean number of apoptotic nuclei detected per mm(2) of the histologic section in the non-necrotic tumor was 8.12 in the prinomastat-treated group and 0.57 in the control group (p < 0.001). Evaluation of the digital images in microscopic sections of the tumors on histologic slides revealed 29.6% necrosis in prinomastat-treated eyes as compared to 10.9% in vehicle-treated eyes (p = 0.003).
CONCLUSIONS
These results suggest that prinomastat treatment significantly reduces the take rate and the growth rate of xenograft in uveal melanoma rabbit model.
Topics: Animals; Antineoplastic Agents; Apoptosis; Enzyme Inhibitors; Fundus Oculi; Humans; Matrix Metalloproteinase Inhibitors; Melanoma, Experimental; Mice; Mice, SCID; Neoplasm Transplantation; Organic Chemicals; Rabbits; Transplantation, Heterologous; Uveal Neoplasms
PubMed: 12187478
DOI: 10.1076/ceyr.24.2.86.8159 -
Journal of Clinical Oncology : Official... Feb 2005Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy.
PATIENTS AND METHODS
Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients.
RESULTS
Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients.
CONCLUSION
Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Organic Chemicals; Protease Inhibitors
PubMed: 15681529
DOI: 10.1200/JCO.2005.03.170 -
The Journal of Biological Chemistry Mar 2012Human cytochrome P450 2D6 contributes to the metabolism of >15% of drugs used in clinical practice. This study determined the structure of P450 2D6 complexed with a...
Human cytochrome P450 2D6 contributes to the metabolism of >15% of drugs used in clinical practice. This study determined the structure of P450 2D6 complexed with a substrate and potent inhibitor, prinomastat, to 2.85 Å resolution by x-ray crystallography. Prinomastat binding is well defined by electron density maps with its pyridyl nitrogen bound to the heme iron. The structure of ligand-bound P450 2D6 differs significantly from the ligand-free structure reported for the P450 2D6 Met-374 variant (Protein Data Bank code 2F9Q). Superposition of the structures reveals significant differences for β sheet 1, helices A, F, F', G", G, and H as well as the helix B-C loop. The structure of the ligand complex exhibits a closed active site cavity that conforms closely to the shape of prinomastat. The closure of the open cavity seen for the 2F9Q structure reflects a change in the direction and pitch of helix F and introduction of a turn at Gly-218, which is followed by a well defined helix F' that was not observed in the 2F9Q structure. These differences reflect considerable structural flexibility that is likely to contribute to the catalytic versatility of P450 2D6, and this new structure provides an alternative model for in silico studies of substrate interactions with P450 2D6.
Topics: Catalytic Domain; Crystallography, X-Ray; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Enzyme Inhibitors; Humans; Ligands; Models, Molecular; Organic Chemicals; Protein Binding
PubMed: 22308038
DOI: 10.1074/jbc.M111.307918 -
Clinical Cancer Research : An Official... Feb 2004Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor... (Clinical Trial)
Clinical Trial
PURPOSE
Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.
EXPERIMENTAL DESIGN
Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.
RESULTS
The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K(i) for MMPs 2 and 9 were achieved at all of the dose levels.
CONCLUSIONS
Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10-100-fold greater than the K(i) (in vitro inhibition constant) for the targeted MMPs (2 and 9).
Topics: Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Agents; Area Under Curve; Disease Progression; Enzyme Inhibitors; Female; Humans; Kinetics; Male; Matrix Metalloproteinase Inhibitors; Maximum Tolerated Dose; Middle Aged; Organic Chemicals; Time Factors
PubMed: 14871966
DOI: 10.1158/1078-0432.ccr-0981-3 -
Thrombosis and Haemostasis Oct 2003Two clinical trials have suggested that the combination of vascular endothelial growth factor inhibitor with chemotherapy is associated with venous thromboembolism... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
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.
Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Organic Chemicals; Placebos; Retrospective Studies; Risk; Thromboembolism; Venous Thrombosis
PubMed: 14515196
DOI: 10.1160/TH03-01-0041 -
ACS Biomaterials Science & Engineering Mar 2017Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional...
Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional therapy. Prinomastat targets the essential matrix metalloproteinase degradation of the extracellular matrix needed for cancer invasion; however, its clinical potential is impeded by adverse musculoskeletal side effects. By localizing delivery of prinomastat via cyclodextrin polymers, systemic side effects can be bypassed. In this letter, we demonstrate that prinomastat delivery from β-cyclodextrin polymers results in months-long inhibition of MMPs as measured by gelatin zymography, more appropriately addressing the time frame of cancer cell invasion.
PubMed: 33465922
DOI: 10.1021/acsbiomaterials.6b00626