Inhibition of Angiogenesis and Murine Hemangioma Growth by Batimastat, a Synthetic Inhibitor of Matrix Metalloproteinases

Taraboletti, Giulia; Garofalo, Angela; Belotti, Dorina; Drudis, Teresa; Borsotti, Patrizia; Scanziani, Eugenio; Brown, Peter de Nully; Giavazzi, Raffaella

doi:10.1093/jnci/87.4.293

Cited by 212 publications

(99 citation statements)

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“…1). Similar anti-invasive properties have previously been reported with other hydroxamic acid based MMPIs [35][36][37] and TIMPs [38][39][40], as well as with anti-gelatinases anti-bodies [39,41]. Because a reduced invasiveness could result from a cytotoxic effect of the inhibitor, cellular viability and metabolism were measured by the WST-1 assay after 48 h of treatment.…”

Section: Anti-invasive Activity Of Gi129471 On Ht1080 Cellssupporting

confidence: 64%

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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Enhanced expression and activation of matrix met-alloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with β-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as 11-1β and TNF-α were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-Spectrum MMPIs.

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Section: Anti-invasive Activity Of Gi129471 On Ht1080 Cellssupporting

confidence: 64%

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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“…For invasion, filters were coated with a thick layer of the reconstituted basement membrane Matrigel (Beckton Dickinson, Bedford, MA, USA; 0.5 mg ml À1 ) that cells have to degrade in order to reach and migrate through the filter. In this assay, invasion is prevented by inhibitors of matrix-degrading proteases, which do not affect chemotaxis (Taraboletti et al, 1995), therefore proving the true functional distinction between the assays of invasion and chemotaxis. Human umbilical vein endothelial cells were detached and treated with vehicle or aplidine (0.03 -10 nM) for 1 h at 371C in DMEM -0.1% BSA.…”

Section: Endothelial Cell Motility and Invasion Assaysmentioning

confidence: 74%

Antiangiogenic activity of aplidine, a new agent of marine origin

et al. 2004

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The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF-and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.

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“…This indicates that batimastat inhibition occurred at > 10 days of tumour growth, possibly during the phase when neovascularisation may have been maximal. In a previous model it has been shown that batimastat has the potential to inhibit angiogenesis (Taraboletti et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model

Watson

Morris²,

Parsons³

et al. 1996

Br J Cancer

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Summary The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of C170HM2 cells into the peritoneal cavity of SCID mice and resulted in solid tumour deposits and ascites formation. The cell line expressed both the 72 and 92 kDa forms of gelatinase by zymography. Batimastat administered from day 0 (40 mg kg-1) reduced the volume of ascites to 21 % of control in mice treated from day 0 (P <0.002) but not day 10. Formation of solid peritoneal deposits was significantly reduced to 77% of vehicle control when batimastat was administered from day 0 (P<0.01) and 69% of control when administered from day 10 (P<0.05). Thus, batimastat has the ability to reduce the volume of ascites forming in SCID mice injected intraperitoneally with the human colorectal cell line, C170HM2, when administered from day 0 but not from day 10. Solid peritoneal tumour deposits were significantly reduced in both treatment groups, highlighting the therapeutic potential of batimastat in this clinical condition.Keywords: metalloproteinase; colorectal cancer; batimastat A large body of evidence now suggests that matrix metalloproteinases (MMPs) play a role in the metastasis of tumour cells (Brown, 1993). Secretion of these enzymes by both normal and malignant cells is in the form of a latent precursor, which is activated by removal of an amino terminal domain (Stetler-Stevenson et al., 1989). These enzymes are implicated in the breakdown of extracellular matrix and vascularisation, which are both critical for successful metastasis, and recent clinical studies have shown MMP to play a role in the spread of human tumour cells Davies et al., 1993).The role of individual enzymes from the MMP family, in both the growth and metastatic spread of colorectal tumours, has been investigated. Activity of type I fibrillar collagenase, a member of the MMP family, has been shown to correlate with histological grade (van der Strappen, 1990). The 72 kDa gelatinase, which breaks down type IV collagenase of basement membrane, correlates with tumour progression, and mRNA studies have revealed the presence of this enzyme in the tissue stroma adjacent to the invasive edge of the cancer (D'Errico et al., 1991; Poulson et al., 1992). The 92 kDa form of gelatinase has been demonstrated by immunocytochemistry to be widespread in colorectal carcinoma, especially in tumours of advanced stage (Jeziorska et al., 1994). In the same study, expression of the enzyme at specific sites in the tumour has been shown to be inversely related to the localisation of type IV collagen. Furthermore, the 92 kDa gelatinase is elevated in the plasma of colon cancer patients (Zucker et al., 1993). In a study evaluating stromelysins 1 and 2 and matrilysin (PUMP-1) expression in colorectal cancer, the mRNA of the latter enzyme was expressed in 75% of colon carcinomas, whereas the mRNA of the former was not detected (McDonnell et al., 1991). In a recent study, stromelysin 3 mRNA was overexpressed in primary col...

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Inhibition of Angiogenesis and Murine Hemangioma Growth by Batimastat, a Synthetic Inhibitor of Matrix Metalloproteinases

Abstract: These results confirm the importance of matrix metalloproteinase in endothelial cell recruitment that occurs in angiogenesis and in the formation of vascular tumors and suggest a therapeutic potential for synthetic matrix metalloproteinase inhibitors.

Cited by 212 publications

References 0 publications

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Antiangiogenic activity of aplidine, a new agent of marine origin

Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model

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