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Prinomastat

About: Prinomastat is a(n) research topic. Over the lifetime, 57 publication(s) have been published within this topic receiving 6032 citation(s). The topic is also known as: AG-3340.


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TL;DR: A new view of the functional role of M MPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors.
Abstract: Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat metastases. One class of molecules that has been repeatedly implicated in metastasis is the matrix metalloproteinases (MMPs). In this review, we re-examine the evidence that MMPs are associated with metastasis and that they make a functional contribution to the process. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex role in metastasis and that they may make important contributions at other steps in the metastatic process. Studies using intravital videomicroscopy, as well as experiments in which levels of MMPs or their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are manipulated genetically or pharmacologically, suggest that MMPs are key regulators of growth of tumors, at both primary and metastatic sites. On the basis of this evidence, a new view of the functional role of MMPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Further clarification of the mechanisms by which MMPs regulate growth of primary and metastatic tumors will be important in the development of novel therapeutic strategies against metastases.

1,555 citations

Journal ArticleDOI
TL;DR: Novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice and it is shown for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340).
Abstract: A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.

714 citations

Journal ArticleDOI
27 Dec 2000-Oncogene
TL;DR: The failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established.
Abstract: Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.

530 citations

Journal ArticleDOI
TL;DR: In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance, and decreased the number of murine melanoma lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol.
Abstract: We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.

235 citations

Journal ArticleDOI
TL;DR: The data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment, and an inhibition in the architecture of the tumor vasculature in M MP-9-deficient mice, resulting in fewer and smaller blood vessels.
Abstract: Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al ., Cancer Res., 58: 2209–2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases ( P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% ( P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections ( P < 0.001), primarily due to the presence of smaller vessels ( P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells ( P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel ( P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.

205 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20211
20201
20171
20132
20123
20101