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Cancer Research Mar 2004Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9, that have been implicated in many steps of tumor progression,...
Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9, that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases (P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% (P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections (P < 0.001), primarily due to the presence of smaller vessels (P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells (P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel (P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.
Topics: Cell Division; Cell Line, Tumor; Disease Progression; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neovascularization, Pathologic; Neuroblastoma; Pericytes
PubMed: 14996727
DOI: 10.1158/0008-5472.can-03-0160 -
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 -
Lung Cancer (Amsterdam, Netherlands) Dec 2003We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly...
Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model.
We studied the synthetic matrix metalloproteinase inhibitor (MMPI) prinomastat (AG3340) in a well-established NCI-H460 orthotopic lung cancer model that exhibits highly predictable regional and systemic metastatic patterns. Both primary and metastatic tumors express the matrix metalloproteinases (MMP-2), MT1-MMP (MMP-14) and tissue inhibitor of metalloproteinases (TIMP-2). The anti-tumor activity of prinomastat was investigated both as a single agent and in combination therapy with carboplatin. Treatment with both carboplatin (at two dose levels) and prinomastat commenced when the primary lung cancer was approximately 200-300 mg in size and without gross or microscopic evidence of metastases. As single agents, prinomastat significantly reduced the incidence of kidney metastasis, but had no effect on metastatic frequency to other organs. As single agents neither drug enhanced length of survival over control animals, although microvessel counts in prinomastat-treated tumors were lower than in tumors from control animals (P<0.01). In combination prinomastat and the lower dose of carboplatin significantly enhanced survival over control animals, and over animals treated with carboplatin alone (P<0.05). Tolerance to this combination was assessed with body weight and serum biochemistries. At the higher carboplatin dose, toxicity became evident both as a single agent and in combination with prinomastat. Our 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.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blotting, Northern; Carboplatin; Cell Line, Tumor; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Organic Chemicals; RNA, Messenger; Random Allocation; Rats; Rats, Nude; Survival Rate; Tissue Inhibitor of Metalloproteinases; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 14644522
DOI: 10.1016/s0169-5002(03)00355-6 -
Bioorganic & Medicinal Chemistry Dec 2003The design, synthesis, and structure-activity relationship (SAR) of a series of novel nonpeptidic cyclic phosphon- and phosphinamide-based hydroxamic acids as inhibitors...
The design, synthesis, and structure-activity relationship (SAR) of a series of novel nonpeptidic cyclic phosphon- and phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases MMP-1, MMP-3, and MMP-9 are presented. Based on modelling studies and X-ray analysis, a model of the binding mode of these novel compounds in the MMP active site was obtained. This model provided a rational explanation for the observed SAR data, which included a systematic study of different S1' directed substituents, zinc-complexing groups, chirality, and variation of the cyclic phosphon- and phosphinamide rings. The in vivo effect of four compounds in a human fibrosarcoma mouse model (HT1080) was evaluated and compared to that of a reference compound, Prinomastat. Inhibition of tumour growth was observed for all four compounds.
Topics: Amides; Animals; Antineoplastic Agents; Binding Sites; Cell Division; Crystallography, X-Ray; Drug Design; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Matrix Metalloproteinase Inhibitors; Mice; Mice, Nude; Models, Animal; Models, Molecular; Molecular Structure; Organophosphonates; Protease Inhibitors; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 14642591
DOI: 10.1016/j.bmc.2003.09.015 -
Lung Cancer (Amsterdam, Netherlands) Dec 2003It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently... (Review)
Review
It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Humans; Lung Neoplasms; Neovascularization, Pathologic; Survival Analysis; Treatment Outcome
PubMed: 14611919
DOI: 10.1016/s0169-5002(03)00308-8 -
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 -
Methods and Findings in Experimental... 2003Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABT-510, ABX-EGF, acetyldinaline, ACIDFORM, acyline, afeletecan hydrochloride, anecortave acetate, apolizumab, l-arginine hydrochloride, asimadoline, atazanavir sufate, atlizumab; BMS-181176, BMS-188667; CAB-175, carnosine, CDP-870, CEP-701, CEP-7055, CGC-1072, ChimeriVax-JE, ciclesonide, cilomilast, clofarabine, combretastatin A-4 phosphate, cryptophycin 52; Duloxetine hydrochloride; E-5564, eculizumab, elcometrine, emtricitabine, ENO, epratuzumab, eszopiclone, everolimus; Fampridine, flurbiprofen nitroxybutyl ester; Garenoxacin mesilate, gestodene, GI-181771, gimatecan, gomiliximab; Halofuginone hydrobromide, hGH, hLM609; ICA-17043, IL-1 receptor type II, IMC-1C11, iodine (I131) tositumomab, irofulven, ISAtx-247; J591; L-778123, lanthanum carbonate Lasofoxifene tartrate, LDP-02, LE-AON, leteprinim potassium, lintuzumab, liraglutide, lubiprostone, lumiracoxib, lurtotecan, LY-450108, LY-451395; MAb G250, magnesium sulfate, MDX-210, melatonin, 2-methoxy-estradiol, monophosphoryl lipid A; NM-3, nolpitantium besilate; Ocinaplon, olpadronic acid sodium salt, oral heparin; Palonosetron hydrochloride, pemetrexed disodium, PI-88, picoplatin, plevitrexed, polyphenon E, pramlintide acetate, pregabalin, prinomastat, pyrazoloacridine; Resiniferatoxin, rhEndostatin, roxifiban acetate; S-18886, siplizumab, sitaxsentan sodium, solifenacin succinate, SU-11248, SU-6668; Talampanel, TAPgen, testosterone transdermal gel, trabectedin; VEGF-2 gene therapy, visilizumab; ZD-6416, ZD-6474.
Topics: Clinical Trials as Topic; Humans
PubMed: 12949633
DOI: No ID Found -
Lung Cancer (Amsterdam, Netherlands) Aug 2003Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix... (Review)
Review
Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.
Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Extracellular Matrix; Humans; Lung Neoplasms; Neovascularization, Pathologic; Treatment Outcome
PubMed: 12867064
DOI: 10.1016/s0169-5002(03)00144-2 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2003The invasion and metastasis of malignant tumor cells are important factors causing the death of cancer patients. The proteolytic activity of proteinases to most of the... (Review)
Review
The invasion and metastasis of malignant tumor cells are important factors causing the death of cancer patients. The proteolytic activity of proteinases to most of the extracellular matrix macromolecules is closely correlated with the invasion and metastasis of malignant tumor cells. Matrix metalloproteinases (MMP) are key proteinases involved in these processes. MMP is a type of Zn(2+)-depended proteinases. MMP2 and MMP9 are the unique types of proteinase that hydrolyze the bone structure of excellulary matrix (type IV collagen). So they are particularly correlated with leukemia cells infiltration and metastasis. This review aims to introduce the function of MMP and the regulation of matrix gene expression, as well as their roles in leukemia cell invasion and metastasis. A new strategy that MMP may be a therapeutic target in the treatment of leukemia is particularly introduced.
Topics: Antineoplastic Agents; Humans; Leukemia; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Oligopeptides; Organic Chemicals; Organometallic Compounds
PubMed: 12844422
DOI: No ID Found -
IDrugs : the Investigational Drugs... Jan 2003
Topics: Animals; Antineoplastic Agents; Genetic Therapy; Globins; Hematologic Diseases; Humans; Membrane Proteins; Metalloendopeptidases; Organic Chemicals; Telomerase
PubMed: 12838960
DOI: No ID Found