Chemically modified tetracyclines as inhibitors of matrix metalloproteinases

doi:10.1016/j.drup.2004.04.002

Drug Resistance Updates

Volume 7, Issue 3, June 2004, Pages 195-208

https://doi.org/10.1016/j.drup.2004.04.002 Get rights and content

Abstract

Matrix metalloproteinases belong to a diverse group of enzymes that are not only involved in restructuring the extracellular matrix, but also play a major role in various pathophysiological conditions by virtue of their complicated expression, activation, and regulation processes. They have been widely implicated to function as major contenders in cancer progression, frequently due to their role in invasion, proliferation and metastasis. MMP inhibitors have been specifically designed to target these altered activities of MMPs, mostly by means of inhibiting their function and by diminishing their increased expression in various disease states, particularly cancer. Tetracyclines and chemically modified tetracyclines (CMTs) have been rationally designed to inhibit the activity of MMPs and thus decrease the potential risk of spread of tumor cells to distant sites by invasion and metastasis. Pre-clinical and early clinical data for one of these CMTs, COL-3 (formerly CMT-3) indicate considerable potential for this group of anticancer agents. Further testing and rational modifications of these CMT analogues might lead to new anticancer agents.

Introduction

There is strong evidence that matrix metalloproteinases (MMPs), a family of enzymes that function to degrade the extracellular matrix (ECM), play a significant role in tumor invasion and metastasis. MMPs are present in healthy individuals, and have been shown to be involved in various physiological and pathological processes. Regulation of MMP gene expression in normal tissues is tightly controlled to limit its biological activity. This activity control is lost in malignancy, and MMPs participate in tumor invasion and metastasis as a result of their capacity to degrade the ECM and regulate angiogenesis (Chambers and Matrisian, 1997, Liotta and Stetler-Stevenson, 1990). Two gelatinases, MMP-2 and MMP-9, which degrade basement membrane type IV collagen and appear essential for cellular invasion, are frequently co-expressed in human cancers. In addition, these enzymes have been associated with the progression of disease in a number of malignancies, including breast, colorectal, gastric, pancreatic and non-small cell lung (NSCL) cancers (Basset et al., 1993, David et al., 1994, Hewitt et al., 1991, Ray and Stetler-Stevenson, 1994, Taniguchi et al., 1992). Previous review articles have described the role of MMP and development of MMP inhibitors in extensive detail. Here, we provide an overview of recent advances in development of tetracycline derivatives as potential inhibitors of MMPs, which have shown promising preclinical and early clinical results.

Section snippets

Matrix metalloproteinases

The MMPs were originally described as the enzymes responsible for dissolution of the tadpole tail. Subsequent studies have shown that MMPs belong to a family of zinc-dependent neutral endopeptidases, which are involved in the degradation of the ECM, an important feature in many normal and abnormal biological conditions (Kleiner and Stetler-Stevenson, 1999, Hidalgo and Eckhardt, 2001, Nagase and Frederick-Woessner, 1999). Apart from the primary function of remodeling the ECM, MMPs have been

MMP inhibitors (MMPIs)

As has been evident from pre-clinical and clinical data, if the MMPs have a pivotal role in the process of invasion, metastasis and cancer progression, then the pharmacologic inhibition of MMP activity may be of therapeutic benefit to patients with cancer. As outlined in Fig. 1, there are several potential targeting strategies, which could be employed for reducing MMP activity, particularly at stages of transcription from MMP gene to MMP mRNA and during translation of mRNA into pro-MMP during

Tetracyclines

Tetracyclines (TC), apart from their established role as classical antibiotics, have been shown to inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. The original research directed towards explaining how diabetes increases the severity of periodontal diseases, led to the conclusion that diabetes produces a cascade of abnormalities in collagen metabolism in periodontal and other tissues, including enhanced collagen breakdown, suppressed intracellular collagen

Chemically modified tetracyclines

In a series of in vitro experiments addressing mechanisms, Golub and co-workers investigated the specificity of anti-collagenolytic activity of TCs and located the site on the TC molecule responsible for the host-modulating, non-antimicrobial properties (Golub et al., 1987, Golub et al., 1991, Golub et al., 1992a, Golub et al., 1992b, Golub et al., 1998). Regarding the site of the TC molecule responsible for its anti-MMP activity, these investigators produced the first series of chemically

Development of other CMTs

Newer analogues of CMTs are being identified and assays are being developed to optimize the screening and selection of these compounds (Lokeshwar et al., 2001, Llavaneras et al., 2001). Zymographic analysis has been the most widely used method due to its specificity and has been employed for identifying MMPs from tissue extracts in various studies. This method can be exploited in a way to make it more quantitative by utilizing imaging techniques and can be useful in early screening of various

Resistance to MMPIs

Hosts play different roles in metastasis and molecular pathways in tumor cells are not always equivalent at different metastatic sites. The influence of TGF-beta and chemokines and associated signaling pathways, including the phosphoinositide 3-kinase (PI3K/Akt) pathway, that influence activity of MMP-2, need to be clearly understood as all these may indirectly adversely affect any therapeutic success. It has been shown that blockade of the release of soluble tumor necrosis factor-alpha (TNF-α)

Conclusions and future directions

The MMPs are a large and diverse group of enzymes whose functions in cancer are still emerging. One of the important future prospects is to address the disparity between the MMPs as to why are there so many; is it redundancy or is it because they have different substrates, regulation, tissue expression and biological activity? Should inhibitors that act only on specific MMPs be developed for treatment of cancer? Further exploring these issues would help define a better target for particular

References (126)

A.R. Amin et al.
Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines
FEBS Lett.
(1997)
J.T. Bettany et al.
Tetracyclines induce apoptosis in osteoclasts
Bone
(2000)
H.J. Broxterman et al.
Resistance to cytotoxic and anti-angiogenic agents: similarities and differences
Drug Resist. Update
(2003)
P. D’Agostino et al.
Anti-inflammatory effects of chemically modified tetracyclines by the inhibition of nitric oxide and interleukin-12 synthesis in J774 cell line
Int. Immunopharmacol.
(2001)
P. D’Agostino et al.
Chemically modified tetracyclines induce cytotoxic effects against J774 tumour cell line by activating the apoptotic pathway
Int. Immunopharmacol.
(2003)
R. Fife et al.
Effects of doxycycline on human prostate cancer cells in vitro
Cancer Lett.
(1998)
R.S. Fife et al.
Induction of apoptosis by doxycycline in cultured human osteosarcoma cells
J. Lab. Clin. Med.
(1997)
R.S. Fife et al.
Effects of tetracyclines on angiogenesis in vitro
Cancer Lett.
(2000)
M.K. Gupta et al.
2D-QSAR in hydroxamic acid derivatives as peptide deformylase inhibitors and antibacterial agents
Bioorg. Med. Chem.
(2002)
A. Lauhio et al.
Tetracyclines in treatment of rheumatoid arthritis
Lancet
(1995)

P.J. Morin

Drug resistance and the microenvironment: nature and nurture

Drug Resist. Update

(2003)

H. Nagase et al.

Matrix metalloproteinases

J. Biol. Chem.

(1999)

S. Pinsuwan et al.

Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions

Int. J. Pharm.

(1999)

S. Pinsuwan et al.

Spectrophotometric determination of acidity constants of 4-dedimethylamino sancycline (Col-3), a new antitumor drug

J. Pharm. Sci.

(1999)

V. Poulaki et al.

The role of Fas and FasL as mediators of anticancer chemotherapy

Drug Resist. Update

(2001)

W. Purcell et al.

Development of matrix metalloproteinase inhibitors in cancer therapy

Hematol. Oncol. Clin. North Am.

(2002)

B.I. Ratnikov et al.

Gelatin zymography and substrate cleavage assays of matrix metalloproteinase-2 in breast carcinoma cells overexpressing membrane type-1 matrix metalloproteinase

Lab. Invest.

(2002)

M.A. Rudek et al.

High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma

J. Pharm. Biomed. Anal.

(2000)

P. Basset et al.

Expression of the stomelysin gene in fibroblastic cells of invasive carcinoma of the breast and other human tissues: a review

Breast Cancer Res. Treat.

(1993)

G. Bergers et al.

Effects of angiogenesis inhibitors on multistage carcinogenesis in mice

Science

(1999)

J.T. Bettany et al.

Tetracycline derivatives induce apoptosis selectively in cultured monocytes and macrophages but not in mesenchymal cells

Adv. Dent. Res.

(1998)

L. Blavier et al.

Tissue inhibitors of matrix metalloproteinases in cancer

Ann. N.Y. Acad. Sci.

(1999)

S.K. Boolbol et al.

Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis

Cancer Res.

(1996)

Cancer Trials, 2001. National Cancer Institute...

J.B. Catterall et al.

Assays of matrix metalloproteinases (MMPs) and MMP inhibitors: bioassays and immunoassays applicable to cell culture medium, serum, and synovial fluid

Methods Mol. Biol.

(2003)

A. Chambers et al.

Changing views of the role of matrix metalloproteinases in metastasis

J. Natl. Cancer Inst.

(1997)

J. Chen et al.

Biodistribution of radiolabeled [(3)H] CMT-3 in rats

Curr. Med. Chem.

(2001)

M. Cianfrocca et al.

Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study

J. Clin. Oncol.

(2002)

E. Cillari et al.

Modulation of nitric oxide production by tetracyclines and chemically modified tetracyclines

Adv. Dent. Res.

(1998)

L.M. Coussens et al.

MMP inhibitors and cancer: trials and tribulations

Science

(2002)

S. Curran et al.

Matrix metalloproteinases in tumor invasion and metastasis

J. Pathol.

(1999)

L. David et al.

Expression of laminin, collagen IV, fibronectin, and type IV collagenase in gastric carcinoma. An immunohistochemical study of 87 patients

Cancer

(1994)

W. Duivenvoorden et al.

Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by human bone-metastasizing cancer cells

Invasion Metast.

(1997)

M. Egeblad et al.

New functions for the matrix metalloproteinases in cancer progression

Nat. Rev. Cancer

(2002)

K.K. Eklund et al.

Tetracycline derivative CMT-3 inhibits cytokine production, degranulation, and proliferation in cultured mouse and human mast cells

Ann. N.Y. Acad. Sci.

(1999)

R. Fife et al.

Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells

J. Lab. Clin. Med.

(1995)

B. Fingleton et al.

Matrilysin in early stage intestinal tumorigenesis

APMIS

(1999)

K. Fong et al.

TIMP-1 and adverse prognosis in non-small cell lung cancer

Clin. Cancer Res.

(1996)

W.L. Gabler et al.

Comparison of doxycycline and a chemically modified tetracycline inhibition of leukocyte functions

Res. Commun. Chem. Pathol. Pharmacol.

(1992)

K. Gelmon et al.

Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development?

J. Natl. Cancer Inst.

(1999)

S. Gilbertson-Beadling et al.

The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism

Cancer Chemother. Pharmacol.

(1995)

L.M. Golub

Reduction with tetracyclines of excessive collagen degradation in periodontal and other diseases

N.Y. State Dent. J.

(1990)

L.M. Golub et al.

Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease

J. Periodont. Res.

(1984)

L.M. Golub et al.

Tetracyclines inhibit tissue collagenases. Effects of ingested low-dose and local delivery systems

J. Periodontol.

(1985)

L.M. Golub et al.

Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources

J. Periodont. Res.

(1985)

L.M. Golub et al.

A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity

J. Dent. Res.

(1987)

L.M. Golub et al.

Tetracyclines inhibit connective tissue breakdown: new therapeutic implications for an old family of drugs

Crit. Rev. Oral. Biol. Med.

(1991)

L. Golub et al.

Tetracyclines (TCs) inhibit matrix metalloproteinases (MMPs): in vivo effects in arthritic and diabetic rats and new in vitro studies

Matrix

(1992)

L.M. Golub et al.

Host modulation with tetracyclines and their chemically modified analogues

Curr. Opin. Dent.

(1992)

L.M. Golub et al.

Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms

Adv. Dent. Res.

(1998)

Cited by (130)

Synthesis of microsponges by spray drying TEMPO-oxidized cellulose nanofibers and characterization for controlled release
2023, Journal of Drug Delivery Science and Technology
A Spray Drying process is presented for one-step production of nanostructured microsponges from TEMPO oxidized cellulose nanofibers (TOCNF). Different formulations were prepared by varying both the nanofibers oxidation degree and the relative ratios of branched polyethyleneimine and citric acid, introduced as crosslinkers. The best reaction conditions were achieved using TOCNF containing the highest content of carboxylic groups (1.5 mmol_COOH/g_TOCNF), which produced microparticles with an average diameter below 5 μm, and a good colloidal stability in aqueous dispersion. Physical-chemical characterization was carried out to study the chemical bonds in the microsponges matrix, the swelling degree and drug loading and release. Tetracycline, a broad-spectrum drug with pH-dependent amphoteric feature, was chosen as model molecule. Chemical crosslinking was verified by spectroscopic characterisation, which revealed the formation of amide bonds. The crosslinked microsponges showed a high drug loading efficiency, as opposed to non-cross-linked ones, and a pH-responsivity in terms of swelling and drug release behaviour. Finally, microsponges derived from formulations without citric acid resulted biocompatible, as demonstrated by direct and indirect in vitro tests on gastric cancer cells.
Metastatic spread inhibition of cancer cells through stimuli-sensitive HPMA copolymer-bound actinonin nanomedicines
2022, Nanomedicine: Nanotechnology, Biology, and Medicine
The unresolved task of modern medicine is to prevent metastatic spread during and after the treatment of primary tumors. Here, the design, controlled synthesis, in-depth physicochemical and biological characteristics of a novel panel of well-defined water-soluble copolymer conjugates bearing actinonin intended for advanced drug delivery and inhibition of metastatic spread are described. Three different synthetic approaches were employed to covalently attach actinonin to the N-(2-hydroxypropyl)methacrylamide copolymers to control the release of actinonin to its pharmacologically active form. Actinonin was attached to the polymers via hydroxamate group suppressing its activity during the delivery, with the activity restored after its release in the primary tumors or metastatic foci. Importantly, developed nanosystems with favorable drug release kinetics inhibited the metastatic spread of cancer cells from primary 4T1 tumors into the lungs as well as invasion of B16F10 melanoma cells from circulation into the lungs at the dosage without any sign of toxicity.
Effect of chemically modified tetracycline-8 (CMT-8) on hematology, blood chemistry, cytokines and peripheral blood lymphocyte subsets of healthy dogs
2021, Research in Veterinary Science
Citation Excerpt :
CMT administration has not been previously evaluated in dogs, but other tetracyclines are currently used in veterinary medicine, and their side effects have been widely described (Schulz et al., 2011). In human medicine, toxicity associated to CMT therapy, especially photosensitivity and rash, has been described (Acharya et al., 2004; Dezube et al., 2006; Richards et al., 2011). Photosensitivity and other side effects were not detected in any of the dogs included in the study, suggesting a good tolerance of CMT-8 when given at the doses used in this work.
Tetracyclines are antibiotics widely used in human and veterinary medicine. Effects on the immune system and inflammatory response, including effects on blood leukocytes proliferation and function and in cytokines synthesis, have been described. Chemically modified tetracyclines (CMT) have lost their antimicrobial activity, but maintain these other properties. This study analyzes the effect of chemically modified tetracycline-8 (CMT-8) on the evolution of complete blood count, blood chemistry, the mRNA expression of selected cytokines and peripheral blood lymphocyte subpopulations distribution in healthy dogs. CMT-8 at a dose of 10 mg/kg once daily was administered per os to six healthy dogs. A control group of five healthy dogs, living in the same conditions than dogs treated with CMT-8, received placebo with an identical therapeutic regimen. When given at the doses used in this study, no side effects of CMT-8 were detected, suggesting a good tolerance and a limited toxicity of the drug. Dogs treated with CMT-8 showed a gradual increase in mean corpuscular hemoglobin. The administration of CMT-8 in healthy dogs did not affect blood mRNA expression of IFN-γ, TNFα, IL-4, IL-6, IL-10, IL-12 p40 and IL-13. However, the lymphocytes expressing class II MHC on their surface decreased during the first two weeks of CMT-8 treatment and subsequently increased for the next three months. Considering the absence of antimicrobial properties of the drug, the effects of CMT-8 detected in this study seem to be unrelated to the classical antimicrobial activity attributed to tetracyclines.
Structural analysis of metal chelation of the metalloproteinase thermolysin by 1,10-phenanthroline
2021, Journal of Inorganic Biochemistry
Metalloproteases and their inhibitors are important in numerous fundamental biochemical phenomena and medical applications. The heterocyclic organic compound, 1,10-phenanthroline, forms a complex with transition metal ions and is a Zn²⁺-chelating metalloprotease inhibitor; however, the mechanism of 1,10-phenanthroline-based chelation inhibition has not been fully elucidated. This study aimed to understand the structural basis of zinc metalloproteinase inhibition by 1,10-phenanthroline. Herein, the crystal structure of thermolysin was determined in the absence and presence of 1,10-phenanthroline at 1.5 and 1.8 Å, respectively. In native thermolysin, Zn²⁺ at the active site is tetrahedrally coordinated by His142, His146, Glu166, and water molecule and contains three Ca²⁺ ions, which are involved in thermostability. In the crystal structure of 1,10-phenanthroline-treated thermolysin crystal, seven 1,10-phenanthroline molecules were observed on the surface of thermolysin. These molecules are stabilized by π- π stacking interactions with aromatic amino acids (Phe63, Tyr66, Tyr110, His216, and Try251) or between the 1,10-phenanthrolines. Moreover, interactions with Ser5 and Arg101 were also observed. In this structure, Zn²⁺ at the active site was completely chelated, but no large conformational changes were observed in Zn²⁺ coordination with amino acid residues. Ca²⁺ at the Ca3 site exposed to the solvent was chelated by 1,10-phenanthroline, resulting in a conformational change in the side chain of Asp56 and Gln61. Based on the surface structure, for 1,10-phenanthroline to chelate a metal, it is important that the metal is exposed on the protein surface and that there is no steric hindrance impairing 1,10-phenanthroline access by the amino acids around the metal.
Matrix metalloproteinase inhibitors (MMPIs) as attractive therapeutic targets: Recent progress and current challenges
2021, NanoImpact
Matrix metalloproteinase (MMP) plays an essential role in many physiological and pathological processes. An increase in MMP activity contributes to excessive degradation and remodeling of the extracellular matrix (ECM), which has been correlated with invasion and metastasis of tumors. Matrix metalloproteinase inhibitor (MMPI) has been developed as an attractive therapeutic target for decades, suggesting inspiring therapeutic effects in preclinical studies. However, achieving specificity remains an important challenge in the development of MMPIs, limiting their clinical application and bringing about the risk of biosafety. Nanomaterials can be used as alternative candidates for MMPI design, providing a new strategy for this problem. This report reviewed the research about MMPIs, summarized their MMPs activity regulation mechanisms, and discussed their failures in clinical trials. Furthermore, we outlined several schemes of MMPIs screening and design. Finally, we reviewed the therapeutic application prospects of MMPIs and discussed the remaining challenges and solutions, which may offer new insights for the development of MMPIs studies.
Bond stability of conventional adhesive system with MMP inhibitors to superficial and deep dentin
2019, Journal of the Mechanical Behavior of Biomedical Materials
To evaluate the microshear bond strength (μSBS) to deep (DD) or superficial (SD) dentin (μSBS) overtime, nanoleakage (AG%), degree of conversion (DC%), water sorption (WSp), and solubility (WSl) of an adhesive system [Adper Single Bond 2(ASB)] containing matrix metalloproteinases (MMP) inhibitors [GM1489 (ASB-GM), Batimastat (ASB-BAT), or Chlorhexidine diacetate (ASB-CHX)]. ASB without inhibitor was used as control (CONTROL).
WSp and WSL were calculated based on ISO4049. DC% was analyzed using FT-IR spectroscopy. Dentin discs were used for μSBS evaluation. For AG%, resin-dentin beams were analyzed under scanning electronic microscopy. Data were analyzed using three-way ANOVA (AG% and μSBS) or ANOVA (DC%, WSp, WSl) and Tukey’s HSD test.
ASB-CHX presented the lowest DC%, lowest WSp, and highest WSl. ASB-GM reached the highest immediate μSBS in SD, only different from ASB-CHX. In DD, ASB-BAT and ASB-GM had the highest μSBS, statistically different from ASB-CHX. After twelve months, ASB-GM and ASB-BAT presented higher μSBS in SD when compared to CONTROL and ASB-CHX. In DD, ASB-GM reached the highest value, which was statistically different from CONTROL and ASB-CHX. CONTROL at both dentin depths and ASB-CHX at DD did not maintain bond stability. In SD after 12 months, ASB-BAT and ASB-GM decreased AG%. In DD, only ASB-GM reduced AG%.
The ASB containing Batimastat and GM1489 maintained resin-dentin bond stability after 12 months for both dentin depths, without jeopardizing WSp, WSl, or DC% of the adhesive system. The ASB-GM presented greater μSBS after 12 months when compared with ASB.
Batimastat and GM1489 could be suitable for inclusion as an MMP-inhibitor into Single Bond to improve the bond stability to superficial and deep dentin, without jeopardize the physic-mechanical proprieties.

View all citing articles on Scopus

View full text

Chemically modified tetracyclines as inhibitors of matrix metalloproteinases

Abstract

Introduction

Section snippets

Matrix metalloproteinases

MMP inhibitors (MMPIs)

Tetracyclines

Chemically modified tetracyclines

Development of other CMTs

Resistance to MMPIs

Conclusions and future directions

FEBS Lett.

Bone

Drug Resist. Update

Int. Immunopharmacol.

Int. Immunopharmacol.

Cancer Lett.

J. Lab. Clin. Med.

Cancer Lett.

Bioorg. Med. Chem.

Lancet

Drug Resist. Update

J. Biol. Chem.

Int. J. Pharm.

J. Pharm. Sci.

Drug Resist. Update

Hematol. Oncol. Clin. North Am.

Lab. Invest.

J. Pharm. Biomed. Anal.

Expression of the stomelysin gene in fibroblastic cells of invasive carcinoma of the breast and other human tissues: a review

Breast Cancer Res. Treat.

Effects of angiogenesis inhibitors on multistage carcinogenesis in mice

Science

Tetracycline derivatives induce apoptosis selectively in cultured monocytes and macrophages but not in mesenchymal cells

Adv. Dent. Res.

Tissue inhibitors of matrix metalloproteinases in cancer

Ann. N.Y. Acad. Sci.

Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis

Cancer Res.

Assays of matrix metalloproteinases (MMPs) and MMP inhibitors: bioassays and immunoassays applicable to cell culture medium, serum, and synovial fluid

Methods Mol. Biol.

Changing views of the role of matrix metalloproteinases in metastasis

J. Natl. Cancer Inst.

Biodistribution of radiolabeled [(3)H] CMT-3 in rats

Curr. Med. Chem.

Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study

J. Clin. Oncol.

Modulation of nitric oxide production by tetracyclines and chemically modified tetracyclines

Adv. Dent. Res.

MMP inhibitors and cancer: trials and tribulations

Science

Matrix metalloproteinases in tumor invasion and metastasis

J. Pathol.

Expression of laminin, collagen IV, fibronectin, and type IV collagenase in gastric carcinoma. An immunohistochemical study of 87 patients

Cancer

Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by human bone-metastasizing cancer cells

Invasion Metast.

New functions for the matrix metalloproteinases in cancer progression

Nat. Rev. Cancer

Tetracycline derivative CMT-3 inhibits cytokine production, degranulation, and proliferation in cultured mouse and human mast cells

Ann. N.Y. Acad. Sci.

Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells

J. Lab. Clin. Med.

Matrilysin in early stage intestinal tumorigenesis

APMIS

TIMP-1 and adverse prognosis in non-small cell lung cancer

Clin. Cancer Res.

Comparison of doxycycline and a chemically modified tetracycline inhibition of leukocyte functions

Res. Commun. Chem. Pathol. Pharmacol.

Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development?

J. Natl. Cancer Inst.

The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism

Cancer Chemother. Pharmacol.

Reduction with tetracyclines of excessive collagen degradation in periodontal and other diseases

N.Y. State Dent. J.

Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease

J. Periodont. Res.

Tetracyclines inhibit tissue collagenases. Effects of ingested low-dose and local delivery systems

J. Periodontol.

Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources