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Showing papers on "Prinomastat published in 2006"


Journal ArticleDOI
TL;DR: 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.

67 citations


Journal ArticleDOI
TL;DR: All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy, and 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.
Abstract: 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.

36 citations


Journal ArticleDOI
TL;DR: These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.
Abstract: 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. Birth Defects Research (Part B) 77:95–103, 2006. © 2006 Wiley-Liss, Inc.

9 citations


Patent
28 Jul 2006
TL;DR: In this paper, the authors proposed a method for treating a fatty liver disease or disorder in a patient in need thereof, which comprises administering at least one matrix metalloproteinase ('MMP') inhibitor to the patient.
Abstract: The present invention relates to a method for treating a fatty liver disease or disorder in a patient in need thereof. The method comprises administering at least one matrix metalloproteinase ('MMP') inhibitor to the patient. Fatty liver disease or disorders include, for example, NAFLD, NASH, ALD, fatty liver associated with chronic hepatitis infection, TPN, steroid treatment, tamoxifen treatment, gastrointestional operations, diabetes and Reye's Syndrome. The method is particularly useful when the fatty liver disease is associated with TPN and the patient is an infant or when the patient is obese. MMP inhibitors useful in the present invention include, for example, Marimastat, tetracyclines, Prinomastat, Batimastat, BAY 12-9566, AG3340 , BMS-275291, Neovastat , BB-3644, KB-R7785, TIMPl, TIMP2, doxycycline, minocycline, RS-130,830; CGS 27023A, Solimastat, Ro 32-3555, BMS-272591, and D2163. Marimastat is a preferred MMP inhibitor.

6 citations


Patent
28 Jul 2006
TL;DR: In this article, a method for treating a fatty liver disease or disorder in a patient in need thereof is proposed, which comprises administering at least one matrix metalloproteinase (MMP) inhibitor to the patient.
Abstract: The present invention relates to a method for treating a fatty liver disease or disorder in a patient in need thereof. The method comprises administering at least one matrix metalloproteinase (“MMP”) inhibitor to the patient. Fatty liver disease or disorders include, for example, NAFLD, NASH, ALD, fatty liver associated with chronic hepatitis infection, TPN, steroid treatment, tamoxifen treatment, gastrointestional operations, diabetes and Reye's Syndrome. The method is particularly useful when the fatty liver disease is associated with TPN and the patient is an infant or when the patient is obese. MMP inhibitors useful in the present invention include, for example, Marimastat, tetracyclines, Prinomastat, Batimastat, BAY 12-9566, AG3340, BMS-275291, Neovastat, BB-3644, KB-R7785, TIMP1, TIMP2, doxycycline, minocycline, RS-130,830; CGS 27023A, Solimastat, Ro 32-3555, BMS-272591, and D2163. Marimastat is a preferred MMP inhibitor.

5 citations


Journal Article
TL;DR: It is hypothesized that the MMP profile early in the establishment of the xenograft is predominantly pro-neoplastic, whereas that seen later may represent both pro- and anti-NEoplastic mechanisms, the latter emerging in a number of MMP-deficient mouse models.
Abstract: Proc Amer Assoc Cancer Res, Volume 47, 2006 3981 We have found that Prinomastat (AG3340, Agouron Phizer) inhibits MDA-MB-231 xenograft growth in nude mice when administered twice daily (50 or 100 mg/kg) from palpability (approx. day 15) of the xenograft, but loses efficacy when administered 2 weeks later when the xenograft has reached a size of 0.5 cm3. This reflects, perhaps, the relatively poor performance of MMP inhibitors in clinical trials, where bulky established disease is a prerequisite. We hypothesize that the MMP profile early in the establishment of the xenograft is predominantly pro-neoplastic, whereas that seen later may represent both pro- and anti-neoplastic mechanisms, the latter emerging in a number of MMP-deficient mouse models. To better understand the MMPs active in this model and other breast cancer xenografts, we have employed species-specific, quantitative RT-PCR (Lafleur et al, Int. J. Can 2005) and observed that MDA-MB-231 cells in vivo express higher levels of MT1-MMP and MMP-13 than a series of novel human breast cancer xenografts, where tumoural (human) MMP levels were quite low. In contrast, however, stromal (mouse) MMP levels were considerably upregulated in all xenografts tested (MMP-2, -9, 11, 13 and MT1-MMP, but not MT2-MMP). Since MMP-13 levels in the resting mammary fat pad are very low, the induction with xenograft implantation reached many hundreds / thousands of folds, which may make it an attractive target. Stromal MMP-13 and MT1-MMP inductions were confirmed at the protein level. The generalization of stromal MMP upregulation suggest that these are the targets of MMP inhibition in this model, advocating stromal-directed therapy. We also tested the efficacy of Prinomastat on osteolytic bone metastasis generated by intracardiac injection of MDA-MB-231 cells into nude mice. We found a considerable delay in the onset of osteolytic damage, and others have reported similar effects with other MMP inhibitors in this model, as well as in osteolytic PC-3 prostate cancer cells. Species-specific qRT-PCR analysis of bone metastases showed significant upregulation of stromal (mouse) MMP-2, -11, -13 and MT1- and MT3-MMP, but not MMP-9 or MT2-MMP. Unlike the primary tumour scenario, bone metastasis represents a late stage manifestation, and could be a more fruitful environment for testing of MMP inhibitors. In the case of bone metastases, we suggest that MMPs play an important role on the responses of the resident bone cells, and again that these “stromal” cells are the MMP inhibitor targets. We believe that further refinement of the appropriate targets, targeting of the stromal component, more specific MMP inhibitors, and testing in the bone metastasis setting represent viable approaches to breast cancer therapy with MMP inhibition. Sup ported by the Victorian Breast Cancer Research Consortium, the National Health and Medical Research Council, and the Thomaiy Breast Cancer Research Fund, Australia.

1 citations