The Matrix Metalloproteinases and Their Inhibitors in the Treatment of Pancreatic Cancer

Jones, Lucie; Ghaneh, Paula; Humphreys, Michelle J.; Neoptolemos, John P.

doi:10.1111/j.1749-6632.1999.tb09533.x

Cited by 83 publications

(52 citation statements)

References 102 publications

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“…The same approach could also be applicable to a broad spectrum of solid tumors, such as colon cancer, pancreatic cancer, melanoma, and ovarian cancer [23][24][25][26][27] characterized by MMP overexpression. p=0.005 Figure 9 Growth curves of U87 xenografts after transfection of U87 cells with GALV M40, GALV, and GALV N40 prior to inoculation.…”

Section: Discussionmentioning

confidence: 99%

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

Allen

et al. 2003

Gene Ther

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Fusogenic membrane glycoproteins (FMG) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. FMG expression constructs caused massive syncytia formation followed by cytotoxic cell death in glioma cell lines, and antitumor activity has been shown in glioma xenografts. FMG-induced fusion in glioma cells can involve heterologous cell lines including normal astrocytes and fibroblasts, therefore making targeting important. Here we report on the use of matrix metalloproteinase (MMP) cleavable linkers to target cytotoxicity of FMGs against gliomas. Expression constructs were made expressing the hyperfusogenic version of the Gibbon Ape Leukemia Virus envelope glycoprotein (GALV) linked to a blocking ligand (the C-terminal extracellular domain of CD40 ligand) via either an MMP cleavable linker (GALV M40), a factor Xa protease cleavable linker (GALV X40), or a noncleavable linker (GALV N40). Unmodified GALV expressing constructs were used as positive controls. The glioma cell lines U87, U118, and U251 previously characterized by zymography and MMP-2 activity assay as high, medium, and low MMP expressors, respectively; normal human astrocytes and the MMP-poor cell line TE671 were transfected with the GALV, GALV N40, GALV X40, and GALV M40 constructs. In contrast to unmodified GALV constructs, transfection with GALV X40 and GALV N40 constructs blocked fusion and cytotoxic cell death. Fusion occurred, however, after transfection with constructs containing MMP cleavable linkers to an extent dependent on MMP expression in the specific cell line. Use of the broad-spectrum MMP inhibitors, 1,10-phenanthroline and N-hydroxy-piperazine-carboxamide completely abolished the ability of MMP constructs to induce fusion. In cell mixing experiments, mixing of MMP-poor cell lines transfected with GALV M40 constructs with the MMP overexpressing untransfected U87 glioma cells led to partial restoration of fusion. Use of U87 supernatant did result in a similar effect. Establishment of stable tranfectants expressing the membrane-type MMPs, MT-1 MMP and MT-2 MMP did restore fusion in the MMP-poor cell line TE671 after transfection with GALV M40, thus indicating that both membrane-type MMPs and soluble MMPs activate the MMP cleavable constructs. In addition, the GALV M40 construct retained its cytotoxic activity against U87 cells in vivo, although less effectively as compared to unmodified GALV. Our data indicate that GALV-induced cytotoxicity in glioma cell lines can be blocked by display of the CD40 ligand. Incorporation of an MMP cleavable linker can selectively restore cytotoxicity in MMP expressing glioma cell lines both in vitro and in vivo, while sparing normal human astrocytes. Given the high frequency of MMP overexpression in gliomas, this represents a promising targeting strategy. Gene Therapy (2003) 10, 725-732.

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Section: Discussionmentioning

confidence: 99%

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

Allen

et al. 2003

Gene Ther

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“…22 Recently, the crucial role of MMPs in cancers has also generated considerable interest in the use of broad-spectrum synthetic MMP inhibitors as potential therapeutic agents for clinical use. [23][24] Because there may be an organ-or cell-specific expression of certain members of the MMP family in each malignant tumor, future efforts should be focused on selecting the most appropriate inhibitor for each tumor type to determine which MMP to target to obtain the best effect with the fewest side effects.…”

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confidence: 99%

Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin

et al. 2003

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Primary neuroendocrine carcinoma (PNC) of the skin is the currently favored designation for the tumor originally described by Toker in 1972 as trabecular carcinoma, 1 and subsequently termed Merkel cell carcinoma on the basis of the electron microscopic findings of neurosecretory granules. 2 PNC is a rare, highly malignant neuroendocrine tumor that occurs most commonly in elderly Caucasian patients. Clinically, it usually appears as a rapidly growing nodule on sundamaged skin of the head and neck region and on the extremities, often being indistinguishable from other cutaneous neoplasms on clinical grounds alone. Affected patients have a high risk of disease progression: early local recurrences occur in about 33% of cases, and approximately 50% of patients will develop regional lymph node metastases with eventual death due to systemic dissemination in more than 33% of cases. [3][4] Because of its rarity, prognostic factors have not been fully established. However, cumulative data from small series have suggested that stage, size of the primary tumor, and gender may have an influence on survival, whereas the prognostic impact of anatomic location and age are more controversial. [5][6][7][8] Although various factors can determine the aggressiveness of PNCs, the capacity for invasion and metastasis of tumor cells, involving the degradation of components of basement membranes and the extracellular matrix, is certainly important. The matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes 9,10 involved in the degradation of different components of the extracellular matrix. At present, there is considerable evidence indicating that MMPs play important roles in local invasion and tumor spread. [10][11][12] The family of human MMPs comprises several members classified into 4 main classes according to their structure and in vitro substrate specificity: collagenases, gelatinases, stromelysins, and membrane-type MMPs [11][12] (Table 1).Tissue inhibitors of matrix metalloproteinases (TIMPs) are the major natural inhibitors of MMPs. To date, 4 types of TIMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) have been recognized. The TIMPs are secreted proteins that complex MMPs and are involved in the inhibition of individual MMPs and regulation of their activity. 13 Indeed, it is thought that the balance between activated MMPs and TIMPs determines the

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“…Collectively, they are able to degrade all components of the extracellular matrix (Jones et al, 1999). MMP activity is regulated by four specific tissue inhibitors of the metalloproteinases (TIMPs) (Greene et al, 1996;Sellers et al, 1997;Stetler-Stevenson, 1989;Uria et al, 1994).…”

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confidence: 99%

A phase II trial of marimastat in advanced pancreatic cancer

et al. 2001

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Summary Pancreatic cancer has a poor response to conventional chemotherapy and radiotherapy. Inhibition of matrix metalloproteinase activity involved in tumour invasion and metastases is a novel biological approach for cancer treatment. This multicentre phase II clinical trial assessed marimastat, an oral matrix metalloproteinase inhibitor, in patients with advanced pancreatic cancer. A total of 113 patients received marimastat for 28 days at 100 mg b.d. (n = 9), 25 mg o.d. (n = 90) or 10 mg b.d. (n = 14). Patients with a response to treatment could continue marimastat beyond 28 days. Of 113 patients, 90 (80%) completed the 28-day study and 83 (73%) continued treatment. The principal side effect was arthralgia in 14 (12%) patients at 28 days and 33 (29%) patients over the whole study. There were 31 patients (27%) who required dose modification. Of 76 patients with evaluable CA19-9 levels, 23 (30%) showed no increase or fall in CA19-9. Of 83 patients with radiologically assessable disease, 41 (49%) had stable disease. The median survival was 245 days for those with a stable or falling CA19-9 level 128 days in those with rising CA19-9. The overall survival was 3.8 months. 1865-1870© 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.2168, available online at http://www.idealibrary.com on http://www.bjcancer.com daily dose (Drummond et al, 1995). The aim of this study was to evaluate the effect and define the tolerability of marimastat in patients with advanced pancreatic cancer. MATERIALS AND METHODS Study designThis was a multicentre open phase II pilot clinical trial to assess the effect of 28 days' administration of oral marimastat (British Biotech Pharmaceuticals Ltd, Oxford, UK) in patients with advanced pancreatic cancer with a facility to continue treatment in those patients with a clinical, serological or radiological 'response' to treatment. Marimastat was administered at a dose of 100 mg b.d., 25 mg o.d. or 10 mg b.d. with the option to reduce the dose in the event of toxicity. Patients were recruited from five centres throughout the UK between August 1995 and December 1997. Ethical committee approval was obtained from the research ethics committee at each investigating centre prior to study commencement. Study objectivesThe aims of this study were:1. To evaluate the effect of 28 days' treatment with oral marimastat on tumour size measured by computerize tomography (CT), disease progression was assessed by the level of cancer antigen CA19-9 and pain, mobility and analgesic use scores 2. To define the tolerability of marimastat 3. To assess the tumour response, safety and tolerability in patients treated beyond 28 days. Patient selectionPatients with radiologically and/or histologically/cytologically proven advanced pancreatic cancer were considered for study entry. Inclusion criteria were: (1) patients over 18 years of age; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; (3) estimated survival of at least 3 months and the ability to take food by mouth. Exclusion criteria inc...

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The Matrix Metalloproteinases and Their Inhibitors in the Treatment of Pancreatic Cancer

Cited by 83 publications

References 102 publications

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease–substrate interaction

Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin

A phase II trial of marimastat in advanced pancreatic cancer

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