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The Journal of Clinical Investigation Oct 2006Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In...
Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.
Topics: Actins; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Axitinib; Basement Membrane; Blood Vessels; Carcinoma, Lewis Lung; Collagen Type IV; Endothelium, Vascular; Imidazoles; Indazoles; Insulinoma; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Neovascularization, Pathologic; Organic Chemicals; Pericytes; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Platelet-Derived Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 17016557
DOI: 10.1172/JCI24612 -
FASEB Journal : Official Publication of... Sep 2006Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI) -anchored membrane protein that is highly conserved in mammalian species. PrPc has the...
Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI) -anchored membrane protein that is highly conserved in mammalian species. PrPc has the characteristics of adhesive molecules and is thought to play a role in cell adhesion and membrane signaling. Here we investigated the possible role of PrPc in the process of invasiveness and metastasis in gastric cancers. PrPc was found to be highly expressed in metastatic gastric cancers compared to nonmetastatic ones by immunohistochemical staining. PrPc significantly promoted the adhesive, invasive, and in vivo metastatic abilities of gastric cancer cell lines SGC7901 and MKN45. PrPc also increased promoter activity and the expression of MMP11 by activating phosphorylated ErK1/2 in gastric cancer cells. MEK inhibitor PD98059 and MMP11 antibody (Ab) significantly inhibited in vitro invasive and in vivo metastatic abilities induced by PrPc. N-terminal fragment (amino acid 24-90) was suggested to be an indispensable region for signal transduction and invasion-promoting function of PrPc. Taken together, the present work revealed a novel function of PrPc that the existence of N-terminal region of PrPc could promote the invasive and metastatic abilities of gastric cancer cells at least partially through activation of MEK/ERK pathway and consequent transactivation of MMP11.
Topics: Animals; CD8-Positive T-Lymphocytes; Calcium-Calmodulin-Dependent Protein Kinases; Cell Adhesion; Enzyme Inhibitors; Flavonoids; Humans; Hyaluronan Receptors; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Organic Chemicals; Prions; Stomach Neoplasms; Tumor Cells, Cultured
PubMed: 16877520
DOI: 10.1096/fj.06-6138fje -
Birth Defects Research. Part B,... Apr 2006Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to...
BACKGROUND
Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development.
METHODS
Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities.
RESULTS
Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro.
CONCLUSIONS
These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.
Topics: Animals; Body Weight; Bone and Bones; Eating; Embryo Culture Techniques; Embryo Loss; Embryo, Mammalian; Enzyme Inhibitors; Female; Fetus; Matrix Metalloproteinase Inhibitors; Organ Size; Organic Chemicals; Pregnancy; Rats; Rats, Sprague-Dawley; Uterus
PubMed: 16607633
DOI: 10.1002/bdrb.20073 -
Investigational New Drugs Mar 2006This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma.
PURPOSE
This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with resectable adenocarcinoma of the esophagus that were stage II or greater. The objectives of the trial were to determine pathologic complete response rate (pCR), overall response rate, progression-free survival, pattern of disease relapse, and two-year and overall survival.
PATIENTS AND METHODS
Preoperative staging included computed tomography, endoscopic ultrasound, and, when feasible, laparoscopy. Eligible patients were randomized to preoperative prinomastat or placebo, plus continuous infusion 5-FU, cisplatin, paclitaxel, and concurrent radiotherapy. Esophagectomy was performed on day 71. Adjuvant paclitaxel and prinomastat were available to all study patients.
RESULTS
Between August 2000 and June 2001, 15 of a planned 78 patients were randomized into the trial. One patient after randomization withdrew consent. Fourteen patients, 7 in each arm, completed preoperative treatment and surgery. pCR was achieved in 5 patients; 1/ 7 prinomastat and 4/ 7 placebo. Disease improvement was achieved in 7 patients; 5 /7 prinomastat and 2 /7 placebo. At a median follow-up of 28 months, 7 patients (2 prinomastat, 5 placebo) are alive with no evidence of disease. The primary prinomastat related toxicity was moderate to severe musculoskeletal toxicity interfering with daily function. This toxicity was managed with treatment rest, dose reduction, or discontinuation. Five patients (3 prinomastat and 2 placebo) had life-threatening thrombo-embolic events, which led to early evaluation of safety and efficacy, and subsequent termination of the study.
CONCLUSIONS
All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy. However, early closure of the study due to unexpected thrombo-embolic events precluded any conclusions regarding clinical activity of prinomastat in locally advanced esophageal cancer patients.
Topics: Adenocarcinoma; Combined Modality Therapy; Esophageal Neoplasms; Esophagectomy; Humans; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organic Chemicals; Protease Inhibitors; Thromboembolism
PubMed: 16502351
DOI: 10.1007/s10637-006-5934-5 -
Bioorganic & Medicinal Chemistry Jun 2006Ab initio calculations (B3LYP/Lanl2DZ level of theory) were performed in this study to determine all the structural and catalytic zinc parameters required in order to...
Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxybiphenyl-4-ylsulfonamido)-3-methylbutanamides.
Ab initio calculations (B3LYP/Lanl2DZ level of theory) were performed in this study to determine all the structural and catalytic zinc parameters required in order to study MMPs and their complexes with hydroxamate inhibitors by means of the AMBER force field. The parameters thus obtained were used in order to study the docking of some known MMPi (Batimastat, CGS 27023A and Prinomastat) and our previously described inhibitor a which had shown an inhibitory activity for MMP-1, and -2, with the aim of explaining the different selectivity. On this basis the two enantiomers (R)-b and (S)-b were designed and synthesized, as more potent MMP-2 inhibitors than our previously described inhibitor a. Between these two enantiomers the eutomer (R)-b proved to be 24.7 times and 15.3 times more potent than CGS 27023A and the parent compound a on MMP-2, maintaining a higher index of MMP-2/MMP-1 selectivity compared with CGS 27023A and the more potent inhibitor Prinomastat. The hydroxamate (R)-b can be considered as a progenitor of a new class of biphenylsulfonamido-based inhibitors that differ from compound a in the presence of an alkyl side chain on the C alpha atom, and show different potency and selectivity profiles on the two MMPs considered.
Topics: Catalysis; Computer Simulation; Crystallography, X-Ray; Drug Design; Humans; Hydrogen Bonding; Hydroxamic Acids; Ligands; Matrix Metalloproteinase Inhibitors; Models, Molecular; Molecular Structure; Organic Chemicals; Organometallic Compounds; Protease Inhibitors; Protein Conformation; Recombinant Proteins; Sensitivity and Specificity; Stereoisomerism; Sulfonamides; Zinc
PubMed: 16483784
DOI: 10.1016/j.bmc.2006.01.056 -
IDrugs : the Investigational Drugs... Mar 2000Agouron Pharmaceuticals is developing AG-3340 (prinomastat), the lead compound in a series of structurally related metalloproteinase inhibitors, for the potential...
Agouron Pharmaceuticals is developing AG-3340 (prinomastat), the lead compound in a series of structurally related metalloproteinase inhibitors, for the potential treatment of cancer and age-related macular degeneration. AG-3340, an oral, non-peptide inhibitor of gelatinase types A and B (MMP-2 and -9), MT1-MP (MMP-14) and collagenase III [234058], was selected following demonstration of activity in a variety of in vivo preclinical models upon oral dosing. In May 1999, phase III trials for lung and prostate cancers of AG-3340 in front-line combination with chemotherapy was begun in the US and Canada [286380,326640]. The tested dose for these trials is 5 to 15 mg bid. Following demonstration of the enhanced efficacy of chemotherapy when supplemented with AG-3340 in preclinical tumor models, pilot combination studies and double-blinded, placebo-controlled phase III trials in 700 patients are in progress for the treatment of non-small cell lung cancer or advanced hormone-refractory prostate cancer [302584,327014]. In August 1999, Agouron initiated a second, confirmatory phase III trial of AG-3340 in combination with chemotherapy in patients with advanced non-small cell lung cancer [337253]. Pharmacokinetic studies have been conducted in healthy male volunteers and single agent dose-escalation studies in patients demonstrated toxicities (grade 1 or 2; joint related) were not doselimiting [302238]. At the 10th European Organization for Research and Treatment of Cancer (EORTC) meeting in Amsterdam (June 1998), Agouron released encouraging results from two phase I studies and one preclinical study of AG-3340 [289688]. In a further 15- patient, phase I study of AG-3340 with paclitaxel and carboplatin, the combination was safe and well tolerated [326268]. AG-3340 has demonstrated significant antimetastatic and antitumor activity in animal models, as well as oral bioavailability and a favorable pharmacokinetic profile. Daily doses of 50 mg/kg completely halted growth of Lewis lung carcinomas in two thirds of test animals and reduced the formation of lung metastasis (0.5 mm in diameter) by 90% [205708]. In December 1997, Roche announced it would discontinue its cancer R&D collaborations with Agouron on AG-3340 as it did not fulfill its scientific and business objectives [271723]. Agouron is investigating analogs of AG-3340 which are undergoing animal studies [332841].
PubMed: 16103944
DOI: No ID Found -
Methods and Findings in Experimental... Jun 2005Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have 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 have been retrieved from the Clinical Trials 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: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine.
Topics: Clinical Trials as Topic; Humans
PubMed: 16082422
DOI: No ID Found -
FASEB Journal : Official Publication of... Sep 2005Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which...
Airway smooth muscle (ASM) proliferation and migration are major components of airway remodeling in asthma. Asthmatic airways are exposed to mechanical strain, which contributes to their remodeling. Matrix metalloproteinase (MMP) plays an important role in remodeling. In the present study, we examined if the mechanical strain of human ASM (HASM) cells contributes to their proliferation and migration and the role of MMPs in this process. HASM were exposed to mechanical strain using the FlexCell system. HASM cell proliferation, migration and MMP release, activation, and expression were assessed. Our results show that cyclic strain increased the proliferation and migration of HASM; cyclic strain increased release and activation of MMP-1, -2, and -3 and membrane type 1-MMP; MMP release was preceded by an increase in extracellular MMP inducer; Prinomastat [a MMP inhibitor (MMPI)] significantly decreased cyclic strain-induced proliferation and migration of HASM; and the strain-induced increase in the release of MMPs was accompanied by an increase in tenascin-C release. In conclusion, cyclic mechanical strain plays an important role in HASM cell proliferation and migration. This increase in proliferation and migration is through an increase in MMP release and activation. Pharmacological MMPIs should be considered in the pursuit of therapeutic options for airway remodeling in asthma.
Topics: Asthma; Basigin; Cell Movement; Cell Proliferation; Cells, Cultured; Humans; Lung; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Myocytes, Smooth Muscle; Organic Chemicals; Stress, Mechanical; Tenascin; Tissue Inhibitor of Metalloproteinase-2
PubMed: 16014803
DOI: 10.1096/fj.04-3350fje -
The Journal of Biological Chemistry Jul 2005We have discovered that clinically tested inhibitors of matrix metalloproteinases can control the functional activity of T cell membrane type-1 matrix metalloproteinase...
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, Kd-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.
Topics: Animals; Antibodies, Monoclonal; Blotting, Western; CD8-Positive T-Lymphocytes; Catalytic Domain; Cell Separation; Enzyme Inhibitors; Flow Cytometry; Hyaluronan Receptors; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Mice; Mice, Inbred NOD; Microscopy, Fluorescence; Organic Chemicals; Pancreas; T-Lymphocytes; Time Factors
PubMed: 15944163
DOI: 10.1074/jbc.M506016200 -
Neuroepidemiology 2005Conventional stroke risks are thought responsible for most cerebral ischemic events (CIE) in adult cancer patients. Also suspected as a risk is cisplatin chemotherapy,...
Conventional stroke risks are thought responsible for most cerebral ischemic events (CIE) in adult cancer patients. Also suspected as a risk is cisplatin chemotherapy, alone or in combination with tumor angiogenesis inhibitor. We investigated whether treatment or tumor characteristics, independently of conventional stroke risks, are associated with CIE in a retrospective cohort study of 1,559 patients with advanced non-small cell lung cancer or hormone-refractory prostate cancer followed during 3 clinical trials of matrix metalloprotease inhibitor (prinomastat) versus placebo, with chemotherapy (gemcitabine/cisplatin, paclitaxel/carboplatin or mitoxantrone/prednisone). During 11,907 patient-months, 28 CIE (17 cerebral infarction, 11 transient ischemic attack) were diagnosed in 24 patients, all but 1 over 55 years. Neither prinomastat, platinum-based chemotherapy nor their combination was associated with CIE after age 55. However, such events were predicted by the presence of distant metastases in the liver or lungs and not in distant lymph nodes (hazard estimate 4.6, 95% CI 2.0-10.5, adjusted for conventional stroke risks). Further studies are needed to verify this preliminary finding and determine its generalizability to advanced tumors other than lung or prostate cancer.
Topics: Aged; Antineoplastic Agents; Brain Ischemia; Cohort Studies; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Organic Chemicals; Prostatic Neoplasms; Retrospective Studies
PubMed: 15832061
DOI: 10.1159/000085172