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The Journal of Thoracic and... Apr 2015Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels... (Comparative Study)
Comparative Study
OBJECTIVE
Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear.
METHODS
Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence.
RESULTS
The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts.
CONCLUSIONS
The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.
Topics: Animals; Azithromycin; Biphenyl Compounds; Bronchiolitis Obliterans; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Graft Survival; Interleukin-12; Interleukin-17; Lung; Lung Transplantation; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Phenylbutyrates; Rats, Inbred F344; Rats, Inbred WKY; Time Factors
PubMed: 25595376
DOI: 10.1016/j.jtcvs.2014.11.088 -
The Journal of Thoracic and... Apr 2015
Topics: Animals; Azithromycin; Biphenyl Compounds; Bronchiolitis Obliterans; Lung; Male; Matrix Metalloproteinase Inhibitors; Phenylbutyrates
PubMed: 25618413
DOI: 10.1016/j.jtcvs.2014.12.051 -
Annals of Oncology : Official Journal... Mar 2001Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We... (Clinical Trial)
Clinical Trial
BACKGROUND
Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity.
PATIENTS AND METHODS
BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks.
RESULTS
Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration.
CONCLUSIONS
The recommended dose for further testing is 800 mg p.o. b.i.d.
Topics: Adult; Amino Acids; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Female; Fibroblast Growth Factor 2; Humans; Lymphokines; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 11332153
DOI: 10.1023/a:1011183905848 -
Annals of Oncology : Official Journal... Mar 2001
Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylbutyrates
PubMed: 11332138
DOI: 10.1023/a:1011198530099 -
British Journal of Pharmacology Dec 2000BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that...
BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP-2, MMP-3 and MMP-9 isozymes. We study the effect of BAY 12-9566 on inflammation and cartilage destruction in adjuvant-induced arthritis (AA) in rats. Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12-9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages. Oral treatment of rats for 22 days with 50 mg kg(-1) body weight/d BAY 12-9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg(-1) body weight/d BAY 12-9566 or 1 mg kg(-1) body weight/d Indomethacin. These results indicate that BAY 12-9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP-2, MMP-3 and MMP-9 are involved in arthritic diseases such as rheumatoid arthritis.
Topics: Amino Acids; Animals; Antineoplastic Agents; Arthritis, Experimental; Biphenyl Compounds; Body Weight; Edema; Hindlimb; Indomethacin; Inflammation; Male; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phenylbutyrates; Rats; Rats, Sprague-Dawley; Weight Gain
PubMed: 11139426
DOI: 10.1038/sj.bjp.0703751 -
Proceedings of the National Academy of... Aug 2002Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental...
Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.
Topics: Adipose Tissue; Angiogenesis Inhibitors; Angiostatins; Animals; Antineoplastic Agents; Biphenyl Compounds; Body Composition; Body Weight; Collagen; Cyclohexanes; Disease Models, Animal; Endostatins; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Organic Chemicals; Peptide Fragments; Phenylbutyrates; Plasminogen; Sesquiterpenes; Thalidomide; Time Factors
PubMed: 12149466
DOI: 10.1073/pnas.162349799 -
Journal of Veterinary Internal Medicine 2007This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study was designed to assess the efficacy of a matrix metalloproteinase inhibitor in prolonging posttreatment survival for dogs with appendicular osteosarcoma after treatment with amputation and doxorubicin chemotherapy.
HYPOTHESIS
Survival will be prolonged in dogs receiving BAY 12-9566.
ANIMALS
The study included 303 dogs with appendicular osteosarcoma.
METHODS
Dogs were treated with doxorubicin (30 mg/m2) every 2 weeks for 5 treatments starting 2 weeks after amputation. Dogs were randomly allocated to receive a novel nonpeptidic biphenyl inhibitor of matrix metalloproteinases (MMPs, BAY 12-9566; 4-[4-4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) or placebo after doxorubicin chemotherapy.
RESULTS
Median survival for all 303 dogs was 8 months; and 1-year, 2-year, and 3-year survival rates were 35%, 17%, and 9%, respectively. Treatment with BAY 12-9566 did not influence survival. Multivariate analysis revealed that increasing age (P = .004), increasing weight (P = .006), high serum alkaline phosphatase (ALP) (P = .012) and high bone ALP (P < .001) were independently associated with shorter median survival times. Additional analyses on available data indicated that as the number of mitotic figures in the biopsy increased (P = .013), and as plasma active MMP-2 concentrations increased (P = .027), the risk of dying increased.
CONCLUSIONS AND CLINICAL IMPORTANCE
Doxorubicin is an effective adjuvant to amputation in prolonging survival for dogs with appendicular osteosarcoma.
Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Cardiomyopathies; Dog Diseases; Dogs; Double-Blind Method; Doxorubicin; Drug Therapy, Combination; Female; Male; Organic Chemicals; Osteosarcoma; Phenylbutyrates
PubMed: 17708400
DOI: 10.1892/0891-6640(2007)21[783:dabftt]2.0.co;2 -
The American Journal of Pathology Mar 2008Previous work has shown that integrin alpha1-null Alport mice exhibit attenuated glomerular disease with decreased matrix accumulation and live much longer than...
Previous work has shown that integrin alpha1-null Alport mice exhibit attenuated glomerular disease with decreased matrix accumulation and live much longer than strain-matched Alport mice. However, the mechanism underlying this observation is unknown. Here we show that glomerular gelatinase expression, specifically matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14, was significantly elevated in both integrin alpha1-null mice and integrin alpha1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin alpha1. Similarly, cultured mesangial cells from alpha1-null mice showed elevated expression levels of all three MMPs, whereas mesangial cells from Alport mice show elevated expression levels of only MMP-9. In both glomeruli and cultured mesangial cells isolated from integrin alpha1-null mice, activation of the p38 and ERK branches of the mitogen-activated protein kinase pathway was also observed. The use of small molecule inhibitors demonstrated that the activation of the p38, but not ERK, pathway was linked to elevated MMP-2, -9, and -14 expression levels in mesangial cells from integrin alpha1-null mice. In contrast, elevated MMP-9 levels in mesangial cells from Alport mice were linked to ERK pathway activation. Blockade of gelatinase activity using a small molecule inhibitor (BAY-12-9566) ameliorated progression of proteinuria and restored the architecture of the glomerular basement membrane in alpha1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.
Topics: Animals; Autoantigens; Biphenyl Compounds; Cells, Cultured; Collagen Type IV; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Integrin alpha1beta1; Matrix Metalloproteinases; Mesangial Cells; Mice; Mice, Knockout; Nephritis, Hereditary; Organic Chemicals; Phenylbutyrates; Tissue Inhibitor of Metalloproteinases; p38 Mitogen-Activated Protein Kinases
PubMed: 18258846
DOI: 10.2353/ajpath.2008.070473 -
International Journal of Cancer Mar 2001The expression of matrix metalloproteinases (MMPs) is often associated with invasiveness or grade of tumours. Increased blood levels of MMP proteins, including MMP-1,... (Clinical Trial)
Clinical Trial
The expression of matrix metalloproteinases (MMPs) is often associated with invasiveness or grade of tumours. Increased blood levels of MMP proteins, including MMP-1, MMP-2, MMP-3 and MMP-9 have been detected in various types of cancers. With the exception of one study, MMPs in serum and plasma have been determined using ELISA. In the present study we measured the activity of the MMPs found in human plasma samples using gelatin enzymography and fluorimetric degradation assays. We used plasma samples from healthy control subjects and cancer patients enrolled in a dose-finding study for the MMP inhibitor, BAY 12-9566, to assess the activity of MMPs found in plasma and screen for efficacy of the MMP inhibitor. BAY 12-9566 has inhibitory activity toward MMP-2, MMP-3 and MMP-9. Patients with advanced solid tumours were enrolled in our study and plasma was collected on day 1 before dosing and at steady-state of the drug on day 15. Our results show that BAY 12-9566 was effective in lowering the plasma gelatinolytic activity in the group of 29 patients when considering the data obtained from a fluorimetric gelatinase assay. The data obtained from gelatin enzymography, however, did not reach significance. The fluorimetric degradation assay could be a useful tool to screen plasma from cancer patients in other clinical trials assessing MMP inhibitors.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biphenyl Compounds; Enzyme Inhibitors; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates
PubMed: 11275992
DOI: 10.1002/1097-0215(200002)9999:9999<::aid-ijc1135>3.0.co;2-m -
Medicina (Kaunas, Lithuania) 2004The cancer cells secrete proteolytic enzymes, which are important in the tumor spreading. The cells must cross basement membrane and extracellular matrix barriers in... (Review)
Review
The cancer cells secrete proteolytic enzymes, which are important in the tumor spreading. The cells must cross basement membrane and extracellular matrix barriers in order to spread. The matrix metalloproteinases are a family of endopeptidases, which enzymatic activity depends on the presence of zinc ion in the catalytic domain. Matrix metalloproteinases hydrolyze extracellular matrix components such as collagen, laminin, fibronectin, proteoglycans and contribute to the spreading of tumor cells by eliminating the surrounding extracellular matrix and basement membrane barriers. This review describes matrix metalloproteinases family classification and structure, their role under physiological conditions and induced proteolysis during pathological processes. There is a balance between proteolytic extracellular matrix degradation and proteolysis inhibition, but under pathological state (e. g. tumor development) the proteolysis becomes uncontrolled. We review tissue inhibitors of matrix metalloproteinases and synthetic matrix metalloproteinase inhibitors, their perspective in cancer treatment; as well as different matrix metalloproteinases expression in patients with tumors and its prognostic significance during cancer progression.
Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Clinical Trials as Topic; Diphosphonates; Disease Progression; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Prognosis; Protease Inhibitors; Thiophenes; Time Factors; Tissue Inhibitor of Metalloproteinases
PubMed: 15630339
DOI: No ID Found