In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models

Sprague, Jennifer; Li, Wen Ping; Liang, Kexian; Achilefu, Samuel; Anderson, Carolyn J.

doi:10.1016/j.nucmedbio.2005.10.011

Cited by 64 publications

(56 citation statements)

References 35 publications

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“…Moreover, the tetrameric peptide exhibited high tumor uptake and prolonged tumor retention in vivo. 25) Although a weak interaction between MMP-2 and cCTT, as indicated by its IC 50 value, was suggested as a cause of low tumor accumulation of cCTT, 10) the multivalent approach using downsized analogs of cCTT may hold potential promise to enhance the affinity of cCTT derivatives for MMP-2. Thus, the downsized analog 1, which has a significant affinity for MMP-2, would be a useful tool for the development of MMP-2-imaging agents.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Mukai

Suganuma

Soejima

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Matrix metalloproteinases (MMPs) comprise a family of enzymes that degrade the basement membrane and extracellular matrix, thus contributing to tissue remodeling and cell migration. 1,2) Numerous studies have demonstrated the various roles of MMPs in pathological processes associated with cancer and atherosclerosis, making MMPs potential targets for diagnosis using noninvasive imaging.3,4) Among MMPs, MMP-2, which degrades a major component of the basement membrane, has been studied extensively and shown to be involved in tumor invasion and metastasis, 5,6) and atherosclerotic plaque rupture. 7,8) For in vivo imaging of MMP-2 activity, we and others used a cyclic decapeptide, cCTTH-WGFTLC (cCTT), as the mother compound because of the clinical and radiopharmaceutical utility of peptide radiopharmaceuticals.9-11) The cyclic decapeptide cCTT was screened as a selective gelatinase (especially MMP-2) inhibitor using phage display technology. Koivunen et al. showed that cyclic decapeptides containing the amino acid sequence His-TrpGly-Phe (HWGF) exhibited selective inhibition toward MMP-2 and MMP-9 activities while a liner peptide containing the HWGF sequence had little inhibitory activity. 10) In tumor-bearing mice, however, both radiolabeled cCTTs exhibited low accumulation in MMP-2-positive tumors. They considered the poor stabilities of these peptides in vivo as one of the causes of low tumor accumulations. Our previously designed compound, 111In-labeled diethylenetriaminepentaacetic acid (DTPA)-conjugated cCTT, showed a good correlation between its tumor accumulation and MMP-2 activity in the tumor, but the accumulations in MMP-2-expressing tumors were relatively low. 11)Oligomers of b-amino acids, b-peptides, have emerged as a promissing class of peptidomimetics. [13][14][15] It is recognized that one of their important characteristics is to form stable secondary structures with as few as four b-amino acid residues. Furthermore, they are entirely stable against proteolytic degradation in vivo. Gademann et al. synthesized a linear b-tetrapeptide analog, Ac-b 3 -HThr-b 2 -HLys-b 3 -HTrp-b 3 -HPhe-NH 2 , to mimic a somatostatin (cyclic 14-mer) in its binding to the human somatostatin receptors, which is known to rest upon a turn containing the amino acid sequence PheTrp-Lys-Thr.16) The turn of the linear b-tetrapeptide analog which has the retro-sequence, is comparable to that of the cyclic a-peptide both in size and orientation of the side chains, although the amide bonds are reversed. These findings led to the design of a linear b-tetrapeptide analog, H-b-His-OH (1), as a downsized derivative to mimic cCTT. In the present study, b-tetrapeptide (1) was prepared by solution-phase synthesis techniques and its inhibitory effect on MMP-2 activity was compared with that of cCTT. To investigate the validity of the drug design, the linear a-tetrapeptides, H-His-Trp-Gly-Phe-OH (2) and H-PheGly-Trp-His-OH (3), were also prepared for comparison (Fig. 1). Results and DiscussionIn general, the preparation of b-amino acids ca...

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Section: Resultsmentioning

confidence: 99%

“…9) Sprague et al recently developed 64 Cu-labeled cCTT as a positron emission tomography (PET) imaging agent. 10) In tumor-bearing mice, however, both radiolabeled cCTTs exhibited low accumulation in MMP-2-positive tumors. They considered the poor stabilities of these peptides in vivo as one of the causes of low tumor accumulations.…”

mentioning

confidence: 96%

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Mukai

Suganuma

Soejima

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Another explanation is that the abundant collagen content and high intradiscal pressure of the discs act as mechanical barriers against tumor invasion. However, metastatic cancer cells secrete matrix metalloproteinases, such as collagenase, that can destroy extracellular matrix components of the discs during metastasis or progression [5,11,17,23]. Therefore, these findings suggest that there may be a mechanism other than the disc's anatomic characteristics that confer its resistance to metastases.…”

Section: Introductionmentioning

confidence: 99%

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells

Park

Lee²,

Cho

et al. 2007

Eur Spine J

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Metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 · 10 6 cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1·, 2·, and 4 · 10 6 cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1·, 2·, and 4 · 10 6 cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dosedependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptoses of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.

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“…For example, Sprague and colleagues reported the design of a 64 Cu-labeled MMP2/9-inhibitory peptide for imaging MMP expression in vivo by PET. Weak tumoral uptake of the probe and high tissue background were observed (38). In addition, many non-peptidyl MMP inhibitors have been used to image A549 tumors by radiolabeled valine-based biphenylsulphonamide MMP inhibitor tumors (39) (41, 42), limiting the specificity of this approach for protease-based prodrug-targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

In VivoPositron Emission Tomography Imaging of Protease Activity by Generation of a Hydrophobic Product from a Noninhibitory Protease Substrate

Chuang

Wang

et al. 2012

Clinical Cancer Research

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Purpose: To develop an imaging technology for protease activities in patients that could help in prognosis prediction and in design of personalized, protease-based inhibitors and prodrugs for targeted therapy.Experimental Design: Polyethylene glycol (PEG) was covalently attached to the N-terminus of a hydrophilic peptide substrate (GPLGVR) for matrix metalloproteinase (MMP) to increase hydrophilicity. PEG-peptide was then linked to a hydrophobic tetramethylrhodamine (TMR) domain and labeled with 18 F to form a PEG-peptide-18 F-TMR probe. Specific cleavage of the probe by MMP2 was tested in vitro by matrixassisted laser desorption/ionization-time-of-flight (MALDI-TOF). In vivo imaging of MMP2-expressing tumors was evaluated by micro-PET.Results: The hydrophobic TMR fragment (948 Da) was specifically generated by MMP2 enzymes and MMP-expressing HT1080 cells but not control MCF-7 cells. MMP-expressing HT1080 cells and tumors selectively accumulated the hydrolyzed, hydrophobic TMR fragment at sites of protease activity. Importantly, we found that 18 F-labeled probe ( 18 F-TMR) preferentially localized in HT1080 tumors but not control MCF-7 tumors as shown by micro-PET. Uptake of the probe in HT1080 tumors was 18.4 AE 1.9-fold greater than in the MCF-7 tumors 30 minutes after injection. These results suggest that the PEG-peptide-18 F-TMR probe displays high selectivity for imaging MMP activity.Conclusions: This strategy successfully images MMP expression in vivo and may be extended to other proteases to predict patient prognosis and to design personalized, protease-based inhibitors and prodrugtargeted therapies.

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In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models

Cited by 64 publications

References 35 publications

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells

In VivoPositron Emission Tomography Imaging of Protease Activity by Generation of a Hydrophobic Product from a Noninhibitory Protease Substrate

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