-
Drugs in R&D Feb 1999
Topics: Adult; Antineoplastic Agents; Colorectal Neoplasms; Drugs, Investigational; Female; Humans; Hydroxamic Acids; Male; Melanoma; Metalloendopeptidases; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Prostatic Neoplasms; Protease Inhibitors; Stomach Neoplasms
PubMed: 10566011
DOI: 10.2165/00126839-199901020-00008 -
Lancet (London, England) Jun 1996
Topics: Biotechnology; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Hydroxamic Acids; Metalloendopeptidases; Patents as Topic
PubMed: 8684093
DOI: No ID Found -
The British Journal of Surgery Aug 1999Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These...
BACKGROUND
Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes have been linked to increased levels of endogenous metalloproteinases (MMPs) within the aorta, particularly MMP-2 and MMP-9. This provides a potential therapeutic target for pharmacological agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of marimastat (an MMP inhibitor) to reduce matrix degradation was assessed in a previously described model of aneurysm disease.
METHODS
Porcine aortic segments (n = 12) were preincubated in exogenous pancreatic elastase for 24 h before culture in standard conditions for 13 days with marimastat 10(-5), 10(-6) and 10(-7) mol/l. Control segments were cultured both without marimastat and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by substrate gel enzymography. The volume fractions of elastin and collagen were determined by stereological analysis of sections stained with Miller's elastin and van Gieson's stain.
RESULTS
Stereological analysis demonstrated preservation of elastin in aorta treated with marimastat at 10(-6) and 10(-5) mol/l; this was significant at the latter concentration (P = 0.007). This was accompanied by a significant reduction in active MMP-2 activity in the samples treated with marimastat 10(-5) mol/l (P < 0.01).
CONCLUSION
Marimastat significantly inhibited elastin degradation and active MMP-2 production within aortic organ cultures.
Topics: Animals; Aortic Aneurysm, Abdominal; Cells, Cultured; Elastin; Enzyme Inhibitors; Extracellular Matrix; Gelatinases; Hydroxamic Acids; Matrix Metalloproteinase 2; Metalloendopeptidases; Swine
PubMed: 10460642
DOI: 10.1046/j.1365-2168.1999.01196.x -
The British Journal of Surgery Oct 1998There is now accumulating evidence that matrix metalloproteinases (MMPs), the physiological mediators of matrix deposition and degradation, play an important role in the...
BACKGROUND
There is now accumulating evidence that matrix metalloproteinases (MMPs), the physiological mediators of matrix deposition and degradation, play an important role in the development of intimal hyperplasia following arterial bypass. This study investigated the effect of marimastat, an orally active specific MMP inhibitor, on neointima formation in cultured human saphenous vein.
METHODS
Segments of human saphenous vein obtained from ten patients undergoing arterial bypass surgery were cultured for 14 days in serum-supplemented RPMI medium (controls) or in control medium supplemented with marimastat at three different concentrations (treatment groups). Following culture, half of each segment was prepared for histological examination and MMPs were extracted from the other half for gelatin zymography.
RESULTS
Marimastat inhibited neointimal thickening in a concentration-dependent manner; inhibition was significant at 10(-5) and 10(-6) mol/l (P=0.006). This observation was paralleled by a significant reduction in the levels of MMP-2 and MMP-9 in the tissues.
CONCLUSION
Marimastat significantly reduced neointimal thickening in this laboratory model. MMP inhibitors may offer a potential therapeutic strategy in the prevention of intimal hyperplasia.
Topics: Cells, Cultured; Enzyme Inhibitors; Graft Occlusion, Vascular; Humans; Hydroxamic Acids; Immunohistochemistry; Saphenous Vein; Tunica Intima
PubMed: 9782017
DOI: 10.1046/j.1365-2168.1998.00888.x -
American Journal of Clinical Oncology Jun 1999Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important... (Clinical Trial)
Clinical Trial
Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important for the growth, spread, and dissemination of most solid malignant tumors. Marimastat is the first orally available MMP inhibitor (MMPI) to be tested in humans and has been shown to inhibit the spread and growth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of marimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively studied 64 patients with advanced carcinoma of the pancreas in whom standard treatments had failed. Eligible patients had a progressive rise in CA 19/9 levels of >25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escalating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) continuation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progression. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and tenderness emerged as dose-limiting toxicity. No other dose-related toxicities were observed. A reduced rate of rise of CA 19/9 was observed at dose levels of 5, 10, and 25 mg twice daily. The overall median survival was 160 days, with a 1-year survival of 21%. Marimastat was associated with an acceptable toxicity profile, and these preliminary data suggest that long-term oral administration is feasible and safe. Doses of 5, 10, and 25 mg twice daily were identified as the optimal doses to be tested in larger randomized studies.
Topics: Adult; Aged; Antineoplastic Agents; CA-19-9 Antigen; Enzyme Inhibitors; Female; Humans; Hydroxamic Acids; Male; Metalloendopeptidases; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Survival Analysis
PubMed: 10362330
DOI: 10.1097/00000421-199906000-00007 -
Medical Science Monitor : International... Aug 2003Marimastat is a potent inhibitor of matrix metalloproteinases and in preclinical studies enhances the anti-tumor activity of certain chemotherapeutics. We performed a... (Clinical Trial)
Clinical Trial
BACKGROUND
Marimastat is a potent inhibitor of matrix metalloproteinases and in preclinical studies enhances the anti-tumor activity of certain chemotherapeutics. We performed a phase I clinical evaluation of the combination of oral marimastat and intravenous paclitaxel, to determine if these drugs could be co-administered safely, and to determine whether marimastat alters paclitaxel pharmacokinetics.
MATERIAL/METHODS
Marimastat was administered twice daily and paclitaxel as a three hour infusion every three weeks. Doses of both marimastat and paclitaxel were escalated in cohorts of patients up to maximal doses of 10 mg for marimastat and 175 mg/m2 for paclitaxel. Paclitaxel plasma pharmacokinetic parameters were assessed in the absence (cycle 1) and presence (cycle 2) of marimastat. Trough marimastat plasma levels were evaluated during cycle 2.
RESULTS
A total of 19 patients were treated at three different dose levels. There were no dose-limiting toxicities during the first cycle of therapy, resulting in dose escalation up to the planned maximal dose for each drug. Neutropenia was the most common significant toxicity at the highest dose level, with grade 3 or higher neutropenia occurring in 38% of patients. There were no complete or partial responses. Pharmacokinetic analyses indicate that marimastat does not alter paclitaxel clearance. At the 10 mg dose, the mean trough marimastat level was 14.8 Kg/L.
CONCLUSIONS
Marimastat and paclitaxel can be co-administered safely at doses equivalent to those recommended for single-agent administration. Additional studies are necessary to determine whether this combination is more effective in controlling tumor progression than paclitaxel alone.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Hydroxamic Acids; Male; Middle Aged; Molecular Structure; Neoplasms; Paclitaxel
PubMed: 12942041
DOI: No ID Found -
Clinical Cancer Research : An Official... Jun 2005To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer.
EXPERIMENTAL DESIGN
Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred.
RESULTS
Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and -0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02).
CONCLUSION
These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.
Topics: Aged; Analysis of Variance; Arthralgia; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Humans; Hydroxamic Acids; Male; Metalloendopeptidases; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Time; Treatment Outcome
PubMed: 15958628
DOI: 10.1158/1078-0432.CCR-04-2252 -
Journal of Clinical Oncology : Official... Nov 2002Increased expression of metalloproteinases is associated with poor prognosis in small-cell lung cancer (SCLC). This trial was undertaken to determine whether adjuvant... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of...
PURPOSE
Increased expression of metalloproteinases is associated with poor prognosis in small-cell lung cancer (SCLC). This trial was undertaken to determine whether adjuvant treatment with the metalloproteinase inhibitor marimastat could prolong survival in responding patients with SCLC after chemotherapy.
PATIENTS AND METHODS
SCLC patients in complete or partial remission were eligible. They were stratified by radiotherapy (early, late, or none), stage (extensive or limited), response (complete or partial), and cooperative group (National Cancer Institute of Canada-Clinical Trials Group or European Organization for Research and Treatment of Cancer). They were randomized to receive marimastat 10 mg or placebo orally bid for up to 2 years.
RESULTS
There were 532 eligible patients (266 marimastat and 266 placebo). Stage was limited for 279 patients (52%) and extensive for 253 (48%). Best response to induction therapy was complete remission for 176 patients (33%), partial remission for 341 (64%), and 15 patients (3%) had undergone surgical resection. The median time to progression for marimastat patients was 4.3 months compared with 4.4 months for placebo patients (P =.81). Median survivals for marimastat and placebo patients were 9.3 months and 9.7 months, respectively (P =.90) Toxicity was generally limited to musculoskeletal symptoms (18% grade 3/4 for marimastat). Dose modifications for musculoskeletal toxicity were required in 90 patients (33%) on the marimastat arm, and 87 (32%) permanently stopped marimastat because of toxicity. Patients on marimastat had significantly poorer quality of life at 3 and 6 months.
CONCLUSION
Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Canada; Carcinoma, Small Cell; Double-Blind Method; Enzyme Inhibitors; Europe; Female; Humans; Hydroxamic Acids; Lung Neoplasms; Male; Metalloendopeptidases; Middle Aged; Patient Compliance; Proportional Hazards Models; Prospective Studies; Quality of Life; Survival Analysis; Treatment Outcome
PubMed: 12431965
DOI: 10.1200/JCO.2002.02.108 -
Lancet (London, England) Jul 1996
Topics: CA-125 Antigen; Enzyme Inhibitors; Female; Humans; Hydroxamic Acids; Metalloendopeptidases; Ovarian Neoplasms; Retrospective Studies
PubMed: 8684209
DOI: 10.1016/s0140-6736(96)24030-9 -
Japanese Journal of Cancer Research :... Jul 2002Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. Even with...
Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. Even with novel approaches such as molecular targeting of cancer chemotherapy, peritoneal dissemination of gastric cancer has little sensitivity to anticancer drugs, and it is impossible to inhibit its growth completely. Intraperitoneal injection of TMK-1 into nude mice at 5 x 10( 5) cells / body resulted in carcinomatous peritonitis that mimicked clinical cases. Continuous administration of marimastat (18 mg / kg / day) from 24 h after the tumor inoculation successfully inhibited the growth of peritoneal dissemination nodules. Combined administration of marimastat (18 mg / kg / day) and mitomycin C (MMC, 2 mg / kg) showed synergistic inhibition of growth of peritoneal dissemination, being superior to MMC alone (2 mg / kg). Although marimastat alone could not increase survival time with statistical significance, combined administration of marimastat and MMC had a survival benefit with statistical significance. The combination of marimastat and MMC increased the preventive effect on peritoneal dissemination. Marimastat seems to be a candidate for the prevention of peritoneal spread of gastric carcinoma.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Body Weight; Cell Survival; Coloring Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Hydroxamic Acids; Male; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Mice, Nude; Mitomycin; Models, Chemical; Neoplasm Metastasis; Neoplasm Transplantation; Peritoneum; Stomach Neoplasms; Tetrazolium Salts; Thiazoles; Time Factors; Tumor Cells, Cultured
PubMed: 12149150
DOI: 10.1111/j.1349-7006.2002.tb01326.x