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Cancer Research Apr 2004Photodynamic therapy (PDT) clinical results are promising; however, tumor recurrences can occur and, therefore, methods for improving treatment efficacy are needed. PDT...
Photodynamic therapy (PDT) clinical results are promising; however, tumor recurrences can occur and, therefore, methods for improving treatment efficacy are needed. PDT elicits direct tumor cell death and microvascular injury as well as expression of angiogenic, inflammatory, and prosurvival molecules. Preclinical studies combining antiangiogenic drugs or cyclooxygenase-2 inhibitors with PDT show improved treatment responsiveness (A. Ferrario et al., Cancer Res 2000;60:4066-9; A. Ferrario et al., Cancer Res 2002;62:3956-61). In the present study, we evaluated the role of Photofrin-mediated PDT in eliciting expression of matrix metalloproteinases (MMPs) and modulators of MMP activity. We also examined the efficacy of a synthetic MMP inhibitor, Prinomastat, to enhance tumoricidal activity after PDT, using a mouse mammary tumor model. Immunoblot analysis of extracts from PDT-treated tumors demonstrated strong expression of MMPs and extracellular MMP inducer along with a concomitant decrease in expression of tissue inhibitor of metalloproteinase-1. Gelatin zymography and enzyme activity assays performed on protein extracts from treated tumors confirmed the induction of both latent and enzymatically active forms of MMP-9. Immunohistochemical analysis indicated that infiltrating inflammatory cells and endothelial cells were primary sources of MMP-9 expression after PDT, whereas negligible expression was observed in tumor cells. Administration of Prinomastat significantly improved PDT-mediated tumor response (P = 0.02) without affecting normal skin photosensitization. Our results indicate that PDT induces MMPs and that the adjunctive use of an MMP inhibitor can improve PDT tumor responsiveness.
Topics: Animals; Cell Line, Tumor; Combined Modality Therapy; Dihematoporphyrin Ether; Drug Synergism; Humans; Isoenzymes; Mammary Neoplasms, Experimental; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Organic Chemicals; Photochemotherapy
PubMed: 15059880
DOI: 10.1158/0008-5472.can-04-0071 -
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 -
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 -
Technology in Cancer Research &... Aug 2004Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular...
Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10(th) day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Capillary Permeability; Cell Division; Cell Line, Tumor; Contrast Media; Enzyme Inhibitors; Female; Homozygote; Humans; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitors; Microcirculation; Neoplasm Transplantation; Neoplasms; Organic Chemicals; Rats; Rats, Nude; Statistics as Topic; Time Factors
PubMed: 15270589
DOI: 10.1177/153303460400300408 -
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 -
Retina (Philadelphia, Pa.) Oct 2004To develop a simple epiretinal membrane (ERM) animal model and evaluate the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase.
PURPOSE
To develop a simple epiretinal membrane (ERM) animal model and evaluate the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase.
METHODS
This experiment was carried out on 18 eyes of nine Brown Norway rats. Preretinal hemorrhage was induced bilaterally using diode laser focused deeply on choroidal blood vessels. One day later, AG3340 was injected intravitreally in the right eyes while the left eyes received equal amounts of vehicle. The developed epiretinal membrane was measured in disk areas and compared between groups.
RESULTS
Clinically, preretinal hemorrhage showed a slow clearance persisting for 8 to 10 weeks. ERM was well established around 12 weeks. Histologically, ERMs consist of fibroblast and glial cells embedded in collagen-rich extracellular matrix infiltrated by macrophages. Seventy-five percent of the hemorrhagic laser burns in the control group developed ERM, whereas only 25% of the hemorrhagic laser burns in treated group developed ERM (P = 0.01). The total surface area of developed ERM was 3.66 DD in treated eyes versus 25.45 DD in control eyes (P = 0.049). The mean surface area of ERM per eye was 0.52 disk areas +/- 1.05 in treated eyes versus 3.18 +/- 3.07 in control eyes.
CONCLUSION
We demonstrated that ERM can be induced on rat retina by simple hemorrhagic retinal laser coagulation. This new animal model could be used for future evaluation of different medical treatment modalities for proliferating ERM. Furthermore, AG3340 demonstrated an inhibitory effect on ERM formation in this new rat model.
Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Epiretinal Membrane; Female; Injections; Laser Coagulation; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Rats; Rats, Inbred BN; Retinal Hemorrhage; Vitreous Body
PubMed: 15492635
DOI: 10.1097/00006982-200410000-00016 -
Current Eye Research Jan 2002To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal...
PURPOSE
To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization.
METHODS
C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research.
RESULTS
AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg.
CONCLUSIONS
AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.
Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hypoxia; Injections, Intraperitoneal; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Organic Chemicals; Pregnancy; Retinal Neovascularization
PubMed: 12187492
DOI: 10.1076/ceyr.24.1.33.5429 -
Current Eye Research Jun 2000To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy...
PURPOSE
To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy (PVR) induced by intravitreal dispase injection.
METHODS
One eye each of 53 New Zealand white rabbits was injected in the vitreous cavity with 0.07 unit of dispase to induce PVR. One week after PVR induction, 53 rabbits were randomized (27:26) to receive 0.5 mg prinomastat or the vehicle of the drug (acidified water) intravitreally every two weeks. The scores of PVR severity (scale of 1-5) were graded to compare the prinomastat-treated animals with the control group.
RESULTS
The average PVR scores in the treatment and control groups were 2.62 and 3.57 respectively (p = 0.038; Wilcoxon rank sum). Clinically significant PVR with retinal detachment (PVR > or = grade 3) developed in 76% of rabbits in the control group versus 51% of rabbits treated with prinomastat.
CONCLUSIONS
Intravitreally administered prinomastat decreased development of PVR in an experimental model which made use of dispase to induce PVR.
Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Enzyme Inhibitors; Epiretinal Membrane; Female; Fundus Oculi; Male; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Rabbits; Retina; Vitreoretinopathy, Proliferative
PubMed: 10980656
DOI: No ID Found -
American Journal of Respiratory Cell... Dec 2001Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the...
Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.
Topics: ADAM Proteins; ADAM17 Protein; Acute Disease; Animals; Antigens, CD; Antigens, Neoplasm; Antineoplastic Agents; Barotrauma; Basigin; Capillary Permeability; Culture Media, Conditioned; Drug Evaluation, Preclinical; Enzyme Induction; Enzyme Inhibitors; Fibroblasts; Injections, Intraperitoneal; Lung; Lung Injury; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Membrane Glycoproteins; Metalloendopeptidases; Models, Animal; Organic Chemicals; Positive-Pressure Respiration; Premedication; Pressure; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Stress, Mechanical; Tumor Necrosis Factor-alpha; Ventilators, Mechanical
PubMed: 11726397
DOI: 10.1165/ajrcmb.25.6.4558f -
The International Journal of Biological... 1999Matrix metalloproteases (MMPs) are a family of structurally related enzymes that are capable of degrading proteins of the extracellular matrix. These enzymes play a role... (Review)
Review
Matrix metalloproteases (MMPs) are a family of structurally related enzymes that are capable of degrading proteins of the extracellular matrix. These enzymes play a role in tissue remodelling associated with both physiological and pathogenic processes. A high expression of MMPs is associated with cancer malignancy: it is related to the tumor's ability to metastasize and to the process of angiogenesis. Treatment with MMP inhibitors alone or in combination with cytotoxic therapy is an interesting novel approach to control tumor progression. The expected mechanism of action of these compounds and the difference in side effects compared to cytotoxic drugs make the definition of endpoints and the assessment of response difficult. Furthermore, it is not yet clear whether tumor vascularization or, more specifically, MMP expression/activation should be a criterion of eligibility for this kind of treatment. This review provides an overview of the characteristics of MMPs and their role in tumor progression, metastasis and angiogenesis. Preclinical and clinical studies with synthetic MMP inhibitors are described. The presence of MMPs in biological fluids of patients and their use in prognostic evaluation and in determining the efficacy of treatment with MMP inhibitors is discussed.
Topics: Animals; Antineoplastic Agents; Azepines; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phenylalanine; Protease Inhibitors; Thiophenes
PubMed: 10669951
DOI: 10.1177/172460089901400406