Matrix Metalloproteinases as Valid Clinical Target - CiteSeerX

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Matrix Metalloproteinases as Valid Clinical Targets Barbara Fingleton* Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: The matrix metalloproteinase family of enzymes has been a pharmaceutical target for over 20 years. In that time, many drugs have been developed but none have successfully passed clinical trials. A significant problem has been development of dose-limiting side-effects that were revealed during long-term clinical trials in diseases such as arthritis and various cancers. There are, however, other clinical settings where evidence for MMP function contributing to the pathophysiology of disease is strong. A number of these settings will be discussed here together with evidence from animal models that MMP inhibition is a valid strategy to be considered. A major advantage with many of these settings is that drug exposure may not have to be long-term and/or systemic thus reducing the possibility that side-effects will stymie MMPI-based therapy.

Key Words: Inflammation, remodeling, acute therapy, topical, cardiovascular disease. INTRODUCTION Drugs that are designed as inhibitors of matrix metalloproteinases (MMPIs) have been around now for almost 25 years yet none have reached clinical utility. The one compound approved for clinical use because of its ability to inhibit MMPs, Periostat™ (CollaGenex Pharmaceuticals, New York, NY) for periodontal inflammation, is a low-dose doxycycline formulation. Cancer and arthritis were once regarded as the prime indications for the use of MMPIs but multiple failed clinical trials in both diseases have had the effect of seriously reducing interest in MMP inhibition as a valid therapeutic approach. Initial clinical testing of MMPIs was started over 20 years ago, before many MMP family members were even identified. As has been discussed in other articles [1-3], there were problems in the design of the clinical trials of these agents, which certainly contributed to their failure. Importantly, however, we have also learned that the target, the MMP family of enzymes, is more complicated than initially thought. In the setting of cancer for example, we now know of many instances where MMPs are apparently protective or anti-tumorigenic and consequently, their large-scale inhibition would likely have unintended consequences. Possibly of most importance for chronic administration was the frequency and severity of dose-limiting sideeffects often affecting musculoskeletal function that occurred in many of the clinical trials. As yet, the cause(s) of these side-effects is unclear. This leads us to a re-evaluation of MMP inhibition as a therapeutic modality. Should MMPs be inhibited and if so, when and how? Despite the massive investments and failed clinical trials there is still reason to believe that the MMPI class of drugs will finally emerge as a useful clinical entity. The predominant reason for this optimism is the recognition that MMPs are contributory in a number of disease states and there are *Address correspondence to this author at the Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA; Tel: (615) 936-5877; Fax: (615) 936-2911; E-mail: [email protected] 1381-6128/07 $50.00+.00

opportunities for targeting them that can avoid the approaches that failed so spectacularly in the past i.e. broadspectrum systemic inhibition over long periods of time. The purpose of this article is to briefly introduce clinical settings where MMP inhibition is likely to be beneficial. For more in-depth information, readers are recommended to refer to comprehensive articles reviewing the roles of MMPs in each of these diseases, which are highlighted in the relevant sections. MMPs - A BRIEF INTRODUCTION MMPs are a family of 25 proteinases, the majority of which are expressed in humans as well as other mammals. Sub-classification can be made on the basis of domain structure or, loosely, on substrate preferences. This latter system is difficult, as the substrate profile for each MMP is not fully established and there is considerable overlap amongst different family members [4]. Nevertheless, we can identify enzymes that are predominantly fibrillar collagenases – MMP1, MMP-8, MMP-13 and MMP-14; gelatinases – MMP-2 and MMP-9; proteoglycanases MMP-3, MMP-7, MMP-10 and an elastase MMP-12. Importantly, MMP substrates are not limited to ECM proteins and in fact, the majority of in vivo-verified substrates are not matrix components [5]. The ability to process molecules such as growth factors, receptors, adhesion molecules, other proteinases and proteinase inhibitors make MMPs potent controllers of events within a microenvironment [6,7]. Since MMPs can affect so many processes, it is not surprising that they are controlled at multiple levels. In most tissues, basal MMP production is normally very low and some stimulus such as injury or growth factor signaling is required to elicit MMP gene transcription. MMPs are initially produced as zymogens and require proteolytic processing to be activated [4]. For certain family members including the membrane-associated MMPs (MTMMPs), MMP-11, MMP-23 and MMP-28 this can be achieved intracellularly by the proprotein convertase furin. For other MMPs however, activation is by other extracellular proteases such as plasmin or even other MMPs. © 2007 Bentham Science Publishers Ltd.

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There is also a family of endogenous inhibitors of MMPs known as tissue inhibitors of metalloproteinases or TIMPs (reviewed in [8]). In general all 4 TIMP proteins can inhibit most MMPs with the exception of TIMP-1 and MT-MMPs. TIMPs bind to MMPs stoichiometrically in a 1:1 manner and, once the levels of MMPs are matched by TIMPs, rampant proteolysis remains checked. In many pathological situations, not only are levels of MMPs increased but TIMP levels are reduced and this disturbed balance in favor of the proteinases frequently correlates with excessive substrate turnover and worsened disease status. There are 2 families of proteinases that are closely related to MMPs by virtue of their catalytic mechanisms, substrates and, in some cases inhibitor binding. These are the ADAM (a disintegrin and metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin) families. ADAMs are generally regarded as sheddases with perhaps ADAM-17, also known as TACE (tumor necrosis factor alpha cleaving enzyme) being the best known. The ADAMTS family includes 2 enzymes, ADAMTS-4 and -5, which are potent aggrecanases and hence play significant roles in cartilage turnover. In this review, we are concentrating specifically on MMPs rather than ADAMs or ADAMTSs, however it is important to be aware that several MMPIs can also affect the activities of members of these families. SYNTHETIC INHIBITORS OF MMPs A large number of chemical entities from many different companies have been described as matrix metalloproteinase inhibitors. Many examples complete with structural information can be seen in the broad-ranging review articles from Whittaker et al. [9] and from Leung et al. [10]. Using information from the drugs database, Table 1 lists some of the compounds that have been described from various companies. Of all these compounds, relatively few progressed to clinical testing. Those that have and the indications for which they have been considered are listed in Table 2. The vast majority of MMPIs are broad-spectrum, that is they can inhibit a large number of MMPs equally well. Some have been described as “selective” meaning that at lower concentrations they will preferentially target some MMP family members rather than others. Inhibition determinations are generally based on solution assays using purified enzymes and may not be entirely representative of the inhibitory capacity in the much more complex in vivo environment. As some MMP as well as ADAM and ADAMTS family members have only recently been discovered there are many MMPIs that were never tested against them. Also, there are other enzyme families containing metal ions in the active sites that could potentially be bound by MMPIs. This is especially true since many of the MMPIs are based on hydroxamate, a chemical chelator that does not show specificity for zinc. For these reasons, the true in vivo inhibitory profile of many drugs is not fully known, thus making it more difficult to determine what inhibitor target is responsible for side-effects.

Barbara Fingleton

stroke (both covered below) or through effects on the vessels themselves. The inner wall of an artery is called the intima and consists of a layer of endothelial cells on a basement membrane. There is then a thick “media” layer that is responsible for the contractility of the vessels. It contains predominantly vascular smooth muscle cells with some macrophages and fibroblasts as well as an extracellular matrix (ECM) rich in fibrillar collagens, various glycoproteins and elastin. The outermost layer, the adventitia, has fibroblasts within a collagen-containing ECM. In response to injury, the intima can expand through deposition of extra matrix as well as migration and proliferation of various cell types. The remodeling of the intima is also associated with inflammatory cell recruitment [11]. These remodeling events can result in major health problems. One of the most serious problems is aneurysm, which refers to a localized area of dilation or widening of a vessel thus weakening the vessel wall. Rupture of an aneurysm is frequently a fatal event. Aneurysms expand as the vessel wall is remodeled by matrix-degrading enzymes and, as one might expect, aneurysm expansion contributes directly to the risk of aneurysm rupture. Over the last several years, there has been a significant literature showing that in human patients MMP levels increase in areas of both abdominal [12-15] and thoracic [16,17] aortic aneurysm and concomitantly, levels of the endogenous inhibitory proteins the TIMPs are reduced [18,19]. A number of different animal models including mice, rats and pigs, have led to a steady accumulation of evidence implicating MMP activity as causal in aneurysm expansion and rupture [20-24]. For example, deficiency of TIMP-1 results in increased and enhanced progression of aneurysm formation in a mouse model [25]. In a complementary study, localized over-expression of TIMP-1 in a rat model prevented aneurysm degeneration and rupture [26]. There are also several studies demonstrating that pharmacological inhibition of MMP activities associated with a reduction in aneurysm expansion. For example the inhibitors RS 132908 (Hoffman-La Roche, Basel, Switzerland) [27], batimastat (British Biotech plc, Oxford, UK) [28] and a panel of chemically modified tetracyclines (CollaGenex Pharmaceuticals) as well as doxycycline [29] all showed efficacy in rat models of aneurysm. While unsuccessful at modulating atherosclerosis or restenosis, the inhibitor CGS 27023A (Novartis AG., Basel, Switzerland) was effective at reducing aneurysm progression in a low density lipoprotein (LDL) receptor deficient mouse model [30]. A phase II clinical trial of doxycycline on patients with small aortic aneurysms indicated that treatment was associated with a gradual reduction of MMP-9 levels however no change was seen in the rate of aneurysm expansion [31]. The investigators suggest that longer term treatment may have benefit. Currently, patients are being recruited for a clinical trial testing whether doxycycline can promote durability of endovascular aneurysm repair 1. Investigators will determine the effects of doxycycline treatment on necessity for reintervention, shrinkage of the aneurysm and serum markers of aneurysm degeneration. A positive result from this trial would be strong support for the use of MMPIs in this clinical scenario.

VASCULAR DISEASE Pathological changes within the vasculature can be dangerous or lethal events by causing myocardial infarction or

1

Adjunctive Treatment with Doxycycline to Enhance the Durability of Endovascular Aortic Aneurysm Repair [Web page]. Available at www.clinicaltrials.gov identifier: NCT00126204. (date accessed 15th September, 2005)

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Table 1.

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A Selection of MMP Inhibitors that have been in Development Within the Past Ten Years

Drug Name

Company

Indication

Description

Phase of Development

AZD-8955

Celltech Group plc/AstraZeneca

OA, arthritis; cancer

MMP and aggrecanase inhibitor

Pre-clinical

CGS-33090A; CGS-35553; CGS-35508; PKF-242-484; PKF-241-466

Novartis AG

Inflammation; arthritis; cancer

dual MMP and TACE inhibitors

Laboratory

CP-471474

Pfizer Inc

MI

MMP inhibitor

Laboratory

FYK-1388

Daiichi Seiyku Co Ltd

arthritis

MMP and TACE inhibitor

Laboratory

Gelastatin A

Korea Research Institute of Bioscience & Biotechnology

Metastasis

MMP-2 inhibitor (from Westerdykella multispora)

Laboratory

KB-R7785

Kanebo KK

Cardiac failure; Graft vs host; diabetes

MMP inhibitors

Laboratory

KT5-12

Kotobuki Seiyaku KK

cancer

Gelatinase selective nonhydroxamate prodrug

Laboratory

MAG-182

Florida State University

Prostate cancer

MMP inhibitor

Laboratory

MAG-283

Florida State University

Arthritis; Corneal ulcer; Cancer

MMP inhibitor

Laboratory

MMI-166

Shionogi & Co Ltd

cancer

Gelatinase selective MMP inhibitor

Pre-clinical

MMP inhibitors

Nippon Organon KK

metastasis; MS; psoriasis, RA; cardiac failure

MMP inhibitors

Laboratory

MMP inhibitors

Bristol-Myers Squibb Pharma Co

inflammation; arthritis

MMP inhibitors

Laboratory

MMP inhibitors

Aventis Pharma SA

infection

anti microbial

Laboratory

MMP inhibitors

Yissum Research Dev Co of the Hebrew University of Jeruslaem

metastasis; cancer

MMP inhibitor

Laboratory

MMP inhibitors

Servier/ University of Montreal

cancer

selective MMP inhibitors (non MMP-1)

Laboratory

MMP inhibitors

LEO Pharma A/S

cancer

selective MMP inhibitors (non MMP-1)

Laboratory

MMP inhibitors

American Cyanamid Co

Metastasis; inflammation

MMP inhibitors

Laboratory

MMP inhibitors

Curis Inc

cancer

recombinant TIMPs

Laboratory

MMP inhibitors

Innapharma Inc

RA; cancer

non-antibiotic tetracycline derivatives

Laboratory

MMP inhibitors

Wyeth Research

OA; RA; atherosclerosis; cancer

selective MMP-9 & MMP-13 inhibitors

Laboratory

PD-166793; PD-169469

Parke-Davis and Co (now Pfizer)

Allergy; congestive heart failure; hypertension

MMP3/MMP2 inhibitors

Laboratory

PGE-4304887; PGE-6912923

Procter & Gamble Co

arthritis

selective MMP inhibitors

Laboratory

PGE-530742

Procter & Gamble Co

MI

selective MMP inhibitor (non MMP-1 & 7)

Laboratory

RS-132908

Hoffman- La Roche

SC-44463

GD Searle & Co (now Pfizer)

Laboratory Cardiovascular disease

MMP inhibitor

Laboratory

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Barbara Fingleton

(Table 1) contd….

Drug Name

Company

Indication

Description

Phase of Development

SC-77964

Pharmacia & Upjohn Inc (now Pfizer)

OA; RA; cancer

MMP-13 inhibitor

Pre-clinical

SS-202

Bristol-Myers Squibb Pharma Co

Inflammation; cancer

MMP inhibitor

Laboratory

UK-383454; UK-370106

Pfizer Inc

OA; arthritis; ulcer; cancer

selective MMP-3 and MMP-13 inhibitors

Laboratory

Table 2.

MMPIs that Progressed to Clinical Testing Druga

Drug Type

Company

Highest Clinical Phase

Indicationsb

Batimastat/ BB-94

Broad spectrum hydroxamate

British Biotech

Phase I

Cancer; restenosis

BB-10153

Broad spectrum hydroxamate

British Biotech

Phase I

MI, stroke

BB-2827

collagenase-targeting, hydroxamate

British Biotech

Phase I

RA

BMS-275291/ D2163

Mercaptoalkylpeptidyl MMP inhibitor, sheddase-sparing

Bristol-Myers Squibb

Phase III

Cancer

CGS-27023A

Broad spectrum, sulfonamide hydroxamate

Novartis

Phase II

Cancer

CMT-3/Col-3/Metastat

chemically-modified tetracycline

CollaGenex

Phase II

Cancer, rosacea, MI

CPA-926

6,7-dihydroxy-coumarin prodrug

Kureha chemical Industry

Phase II

OA

Phase I

Eye disease, COPD,

c

GM6001/Ilomastat/Galardin

Broad spectrum hydroxamate

GlycoMed

Marimastat/ BB-2516

Broad spectrum hydroxamate

British Biotech

Phase III

Cancer

Neovastat/ AE-941

Shark cartilage extract

Aeterna-Zentaris

Phase III

Cancer, psoriasis, macular degeneration

Prinomastat/ AG-3340

Gelatinase-selective hydroxamate

Agouron (Pfizer Global)

Phase III

Cancer, macular degeneration

Ro113-0830

MMP1-sparing,hydroxamate

Roche

Phase II

OA

S-3304

Broad-spectrum, hydroxamate

Shionogi

Phase II

Cancer

Solimastat/ BB-3644

TNF and MMP inhibiting hydroxamate

British Biotech

Phase I

MS, cancer d

Tanomastat/ BAY12-9566

MMP1-sparing, carboxylate

Bayer

Phase III

Trocade/ RO32-3555

collagenase-targeting, hydroxamate

Roche

Phase III

Cancer, OA RA

a

In some cases, drugs have been known by multiple names as they proceeded through development. All known indications are listed, not all necessarily were targeted in the highest clinical phase trials. Originally developed by GlycoMed, now being developed by Arriva Pharmaceuticals and Quick-Med Technologies. d Trials suspended due to safety concerns. b c

In addition to aneurysm, injury and remodeling within vessels, especially on a background of high levels of cholesterol, smoking or other risk factors, leads to the formation of atherosclerotic plaques. These plaques are composed of ECM, smooth muscle cells, endothelial cells and inflammatory cells including so-called foam cells which are lipidladen macrophages [11]. The formation of atherosclerotic plaques within vessels can be a significant cause of heart disease as well as of reduced blood flow to various parts of the body. One of the treatments for atherosclerosis, balloon

angioplasty, involves physical dilatation of the blocked vessel in the region of the plaque thus permitting free blood flow. Unfortunately, this widening of the vessel is regarded as a damage signal and leads to a response including inflammatory cell recruitment and smooth muscle cell migration, which can result in dangerous constriction of the artery, an outcome referred to as restenosis. Restenosis is also associated with the use of stents, wire mesh devices that are placed within vessels at the time of angioplasty with the goal of keeping the vessel open. By one estimate, restenosis oc-

MMPs as Clinical Targets

curs within 3-6 months in 30-50% of patients treated for atherothrombosis [32]. Restenosis is a result of a wound healing process in which multiple proteinases participate. In particular, MMPs-2 and -9 produced by vascular smooth muscle cells are upregulated or induced in response to mechanical injury and hemodynamic stress [33]. The interactions of various cell types together lead to expression of MMPs-1,-3,-7,-8, -11 and -14 [32]. More detail on expression and the cell types involved is given in several recent review articles [32-34]. Mice genetically deficient in either MMP-2 or MMP-9 display defects in smooth muscle migration and neointima formation following vascular injury [35,36]. Gene transfer of either TIMP-1 [37] or TIMP-2 [38] to rat vasculature has been shown to reduce expansion of injured arteries. Pharmacological inhibitors have also shown efficacy with, for example, GM6001 (GlycoMed) blocking stent-induced thickening of vessel walls in rabbits [39]. The chemically-modified tetracycline CMT-3 (CollaGenex) was shown to limit intimal thickening after arterial injury by inhibiting multiple events including both smooth muscle cell proliferation and migration, and accumulation of ECM [40]. The original broad-spectrum MMPI developed by British Biotech was called batimastat but its clinical development was discontinued due to poor oral bioavailability. In an animal model, however, administration of batimastat inhibited constrictive remodeling after balloon angioplasty [41]. More recently, batimastat was resurrected for a joint project with the stent device manufacturer Biocompatibles International plc to test if coating of vascular stents with the MMPI would reduce the restenosis rate [42]. Unfortunately, the results were not as hoped and the project was dropped [43]. There is some suggestion from studies in pigs that inhibiting MMPs after stent placement has no efficacy [44] whereas there is benefit in MMP inhibition after balloon angioplasty [45]. Therefore, future use of MMPIs for restenosis prevention would probably be best in the setting of balloon angioplasty, although this is becoming a much less frequently-used procedure. MYOCARDIAL INFARCTION AND ATHEROSCLEROSIS The term myocardial infarction (MI) refers to an area of cellular damage within the heart muscle. The cause of the infarction is often an occlusion of one of the coronary arteries thus limiting oxygen delivery to the heart. Occlusions are most frequently caused by clots resulting from the rupture of atherosclerotic plaques that have built up in the arteries. Myocardial infarction itself, while it can be a lethal event, is usually survived [34]. However other consequences of infarction such as myocardial rupture and left ventricular dilatation, can be fatal. Almost all of these processes, from the initial development of an atherosclerotic plaque, its rupture, subsequent infarction, through cardiac rupture and left ventricular hypertrophy involve either inflammatory and/or matrix degrading events that are dependent upon MMP activity. For an excellent review of the evidence for the involvement of MMPs and their functions post MI, see the recent article by M.L. Lindsey [34]. MMPs are produced both by infiltrating cells such as macrophages and other leukocytes recruited by the signals of tissue damage, and by cells of the heart especially cardiomyocytes and fibroblasts. In a healthy heart,

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activity of MMPs is controlled by expression of TIMPs, particularly TIMP-4, produced by cardiac cells. This balance is significantly perturbed by infarction or other heart disease and indeed blood levels of MMPs and TIMPs have been correlated with extent of disease. Thus cardiac disease in general is potentially a large target for pharmacological intervention with MMP inhibitors. As with other pathologies, there has to be an appreciation of which MMPs at what time points are appropriate for inhibition. There is certainly plenty of evidence to suggest that MMP activity can be of benefit in some situations but there are also times or patient populations where MMP inhibition may be of greater harm than benefit. An example of the complexity of the situation comes from study of MMP-3. The gene for MMP3 has a naturally occurring promoter polymorphism that involves a run of either 5 or 6 adenines (5A or 6A alleles). This sequence binds differentially to transcription factors, especially NF- B family members, resulting in lowered transcription when the factor is more tightly bound, associated with the 6A sequence and conversely higher MMP3 transcription associated with the 5A sequence [46]. Individuals homozygous for 5A have been found to have higher levels of MMP-3 protein. The consequence of this is not at all straightforward. In MMP-3-null animals, the lack of mmp3 increases atherosclerotic plaque accumulation in high cholesterol apoE-null mice, although aneurysms are less frequent [47]. Similarly, in humans homozygous for the lower expression 6A allele, there is an increased risk for coronary artery disease due to buildup of atherosclerotic plaques. On the other hand, homozygosity for the 5A allele is correlated with instability and rupture of atherosclerotic plaques [48] due to increased macrophage expression of MMP-3. However 5A is also associated with greater elasticity of artery walls and reduced plaque formation [46] . Hence MMP3 genotype may indeed be related to risk for coronary disease but which risk is of more consequence – plaque accumulation with the 5A allele or infarction with the 6A allele? It would appear from epidemiological and genetic studies that the answer depends on other factors. In a study of over 2,700 middle-aged British men, the 5A allele appears to be protective as it is associated with a reduced number of coronary disease events, however this does not hold in smokers [49]. In an American study looking at a slightly different pathology, cardiomyopathy, homozygosity for the 5A allele instead was associated with poorer survival in patients with non-ischaemic cardiomyopathy. It had no bearing on survival in patients with ischaemic cardiomyopathy [50]. The major difference between these studies is that the first deals with a sample population of healthy individuals while in the second the members of the study population were already heart disease patients. Together these data suggest that, in patients with known atherosclerotic plaque accumulation, MMP inhibition may help lower the risk of plaque rupture and subsequent infarction or aneurysm and later perhaps heart failure, however such inhibition is not beneficial to the population as a whole as it could result in increased levels of atherosclerosis. MYOCARDIAL RUPTURE One of the acute complications of myocardial infarction is cardiac rupture, a tear in the heart wall associated with the

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extensive remodeling that must follow an infarction to remove dead tissue and heal the infarcted area. Rupture can occur rapidly after MI and is responsible for a significant percentage of the mortality of hospitalized MI victims. There have been several studies in experimental animals indicating the role of MMPs in rupture and suggesting that MMP inhibition could be a suitable preventative therapy. Gene delivery of TIMP-1 to heart muscle followed by induction of MI showed that in the presence of excess inhibitor, mouse hearts were resistant to rupture [51]. In the same study the authors showed that in MMP-9-deficient mice, remodeling of the myocardium was significantly attenuated following induction of MI and animals were protected from rupture [51]. A recent exciting study by Matsumura et al. described the use of a pharmacological MMP inhibitor to prevent rupture in mice induced to undergo MI by ligation of the left coronary artery [52]. In stark contrast to vehicle-treated wild-type mice, MMP2-deficient or mice treated with an inhibitor were protected from rupture. This was associated with decreased macrophage influx to the infarcted area and thus decreased remodeling of the cardiac wall. In this case, the short-term use of the MMP inhibitor prevented the rupture but also slowed the removal of infarcted cardiomyocytes by macrophages. Since removal of dead cells is a necessary event for healing, it is unknown whether the longer-term consequences of this MMP inhibition would affect heart function. Based on a study comparing TIMP-1 overexpression and MMP-9 deletion as well as genetic deletion of urokinase plasminogen activator (uPA) versus uPA inhibitor overexpression [51], a strong implication is that short-term inhibitor is beneficial but chronic proteinase inhibition may lead to further cardiac damage. Overall indications are that reduction in the MIassociated mortality in the acute setting is a positive outcome and supports the short-term use of MMPIs in post-MI patients. LEFT VENTRICULAR HYPERTROPHY The initial response of the heart to pressure overload as occurs for example in chronic hypertension or following an MI, is to make compensatory changes in the left ventricle to enable pumping of the blood to continue normally. At first, the changes include hypertrophy of the cardiomyocytes and some remodeling of the ECM with the goal of maintaining appropriate contractility in the face of increased pressure. Over a period of time however, the changes are maladaptive rather than beneficial as they are associated with development of fibrosis and ultimately congestive heart failure as pump function falters. It is this process that accounts for the most significant morbidity associated with MI. Since it is a process especially dependent on remodeling, it is not at all surprising that MMPs play significant roles. Several recent articles outline the evidence implicating MMPs in the left ventricular remodeling that follows MI or other physiological triggers [53-55]. Animal models have indicated direct causal roles of MMP activity in the remodeling of the left ventricle. There appears to be somewhat different effects of MMP inhibition on outcome depending on whether the pressure overload was acute or chronic. In animal models, acute pressure overload can be achieved by transverse aortic banding, which increases left ventricular systolic pressure. Studies in various

Barbara Fingleton

genetically-deficient mice and with adenoviruses indicate that deficiency of MMP-9 can attenuate the adverse changes that occur in the left ventricle although not as thoroughly as can deficiency of uPA, an activator of plasmin which in turn is an activator of MMPs [56]. Also adenovirus-mediated overexpression of TIMP-1 can completely abrogate aortic banding-induced heart failure [56]. Together, these data would suggest that multiple MMPs including MMP-9 are critically involved in the pathological changes that occur in the left ventricle prior to congestive heart failure. Additionally Kassiri et al. showed that the absence of TIMP-3 significantly enhanced the heart failure phenotype induced by aortic banding with almost 40% mortality compared to approximately 10% in wildtype mice at 7 weeks [57]. The TIMP-3-null mice could be rescued and even improved over wild-type by a combination of tumor necrosis factor (TNF)alpha ablation and MMP inhibition. Since a primary in vivo function of TIMP-3 appears to be control of ADAM17/TACE-mediated shedding of TNF-alpha, this result was not altogether surprising. Nevertheless, the results indicate that combination approaches targeting multiple molecules implicated in cardiac dysfunction simultaneously would be beneficial. They also suggest a reason why clinical trials of TNF inhibition in congestive heart failure patients have not been successful [58] as inhibition of MMP activity may also be required. The full-scale inhibition of MMPs may however not be warranted in all scenarios. In a study of cardiac biopsies from 36 patients with aortic stenosis, Heymans et al. showed elevated mRNA and protein levels of TIMPs-1 and 2 that correlated with fibrosis development [59]. It is possible that this association between high levels of inhibitors and unfavorable clinical findings may be a function of this being a situation of chronic pressure overload rather than acute as described above. The relationship between TIMPs and fibrosis may also be completely independent of MMP inhibition as it has been known for some time that TIMPs are multifunctional proteins [8]. In fact there is evidence that TIMP-2 can stimulate collagen production by cardiac fibroblasts through a mechanism distinct from MMP inhibition [60] and both TIMPs-1 and -2 can stimulate the proliferation of fibroblasts. Only a direct comparison between synthetic MMPIs and TIMPs over the same period of time will allow determination of whether MMP inhibition is a positive or negative attribute in the setting of chronic pressure overload. A recently completed phase II clinical trial examined the efficacy of the Procter and Gamble compound PG-116800 in patients following their first heart attack 2. The objective was to determine if MMP inhibition would ameliorate the postevent cardiac damage that occurs. Results of this trial are as yet unknown. STROKE Occlusion of the arteries that supply the brain leads to oxygen deprivation, a condition known as cerebral ischemia or stroke. As in many tissues, levels of MMPs are normally

2

Study of Oral PG-116800 Following a Heart Attack [Web page]. Available at www.clinicaltrials.gov Identifier: NCT00067236. (date accessed 15th September, 2005)

MMPs as Clinical Targets

very low in the brain. Results from multiple animal studies indicate upregulation of several MMPs including MMPs-2,-3 and -9 as well as TIMP-3 [61]. Human patients also show increased levels of MMP-9 and MMP-13 that correlate with stroke severity [62-64]. Increased MMP activity correlates with opening of the blood-brain barrier and hemorrhagic transformation [65]. The term ‘blood brain barrier’ describes the endothelial cell layer of cerebral vessels held together by tight junctions, surrounded by a thin basal lamina and pericytes, microglial-type cells that wrap around the vessels. MMPs can disrupt the blood-brain barrier by proteolysis both of the basal lamina and of tight junction proteins such as zonula occludens (ZO)-1 [61]. The opening of the blood brain barrier can be significantly attenuated by systemic administration of MMPIs or in mice genetically deficient in MMP-9 [66,67]. Additionally, MMP activity contributes to expansion of areas of ischemic damage through promoting apoptosis of the neuronal cells on the periphery. Blockade of MMP-9 has been shown to attenuate neuronal cell apoptosis in several models [68-70]. However, as in cardiac damage, long-term inhibition of MMPs may prevent adequate healing of an infarct therefore some caution is necessary when considering chronic MMPI use in stroke victims. A potential use of MMPIs in the acute setting after stroke has been suggested by several investigators [71,72]. This is MMPI given in the context of the clinically approved agent for stroke, recombinant tissue plasminogen activator (rtPA), which must be given within 3 hours of the ischemic event. The rtPA functions to remove the clot and thus allow reperfusion of the ischemic area. If reperfusion is delayed, damage to the blood brain barrier that occurs as a result of the ischemic injury means that reperfusion will unleash significant hemorrhage into the brain. Even when rtPA is used within 3 hours, about 6% of recipients still develop massive edema and die. There is growing evidence that one of the effects of rtPA administration is an increase in levels of MMP-9 [63,73,74]. However, administration of an MMPI prior to the thrombolytic agent prevents significant opening of the blood brain barrier and thus is associated with vastly reduced mortality. Rosenberg and colleagues demonstrated powerful results with this approach in animal models [71]. Another agent used to treat stroke victims is the anti-thrombotic protein heparin, which has also been shown to be associated with cerebral hemorrhage in mice if treatment following ischemia is delayed [75]. The effect is dependent on endogenous tPA as it does not occur in tPA-deficient mice, however the downstream mediator of the tPA appears to be MMP-9 [75]. Hence, there is also a suggestion that an MMPI may be protective in the setting of an antithrombotic in stroke victims. ACUTE LUNG INJURY In acute lung injury, damage occurs in both endothelial and epithelial cells that can seriously compromise the ability of the lung to perform its physiological function i.e. oxygenate the blood. The damage can be due to physical trauma or sepsis but is often exacerbated by the mechanical forces generated during ventilator use. Ventilator use in the absence of trauma such as occurs when surgical patients are put on cardiopulmonary bypass can also lead to lung injury. A most severe form is known as acute respiratory distress syndrome (ARDS), which is classically described as proceeding

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through 3 phases: exudative, proliferative and fibrotic [76]. In the early exudative phase, there is leakage of proteinaceous fluid into the airways as well as migration of inflammatory cells, particularly neutrophils, from the circulation into the lung parenchyma and the alveolar space. In the proliferative and fibrotic stages of the disease, fibroblasts and type II pneumocytes show increased levels of proliferation. The fibroblasts secrete ECM proteins both within the interstitium and, after migration, out in the alveolar space. The fibrotic stage is characterized by excessive deposition of collagens, most frequently types I and III that results in blocking of the airways. Although the primary characteristic of this disease is excessive matrix deposition, there is reason to suspect that proteinase activity may play a role in its pathogenesis. Increased levels of MMPs, particularly MMP2 and MMP-9 have been measured in plasma and in bronchoalveloar lavage (BAL) fluid from patients [77-79]. Increased transcriptional levels of the neutrophil MMPs MMP9 and MMP-8, but not neutrophil elastase, have been detected in samples from patients after cardiopulmonary bypass when compared to pre-bypass samples3. Experimental animals have also shown increased levels of MMPs in response to lung injury. In a pig model, Eichler and colleagues showed increased levels of MMPs-2 and -9 in BAL following time on cardiopulmonary bypass. Using an IgG immune complex-initiated injury model in mice, Warner et al. demonstrated increased levels of MMPs-3 and -9 [80]. They compared the degree of lung injury in wildtype versus MMP-3 or MMP-9 deficient mice and showed that lack of either MMP abrogated the lung injury although by different mechanisms. In the MMP-3-null mice, neutrophil accumulation in the lung was significantly reduced however this was not affected in the MMP-9-null mice. In pig models of cardiopulmonary bypass and endotoxin-induced lung injury, administration of the chemically-modified tetracycline CMT-3 (CollaGenex) was shown to ameliorate the lung damage [81,82]. The drug was particularly effective at blocking neutrophil migration into the lungs, and, as might be anticipated, excessive neutrophil-associated proteolytic activity is a major contributing factor to the pathogenesis of the disease. It should be noted that in these studies, the drug was administered prophylactically and the authors suggest CMT-3 administration as a precaution in critically injured patients at risk of ARDS. A cecal ligation and puncture model of sepsis-induced lung injury in rats similarly showed that CMT-3 reduced lung injury and improved survival in a dose-dependent manner [83]. In a rat model of ventilatorinduced lung injury, pretreatment with the gelatinaseselective MMPI prinomastat (Agouron) also attenuated lung injury [84]. CANCER Five years ago, the proceedings of the oncology community meetings such as the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) were replete with abstracts describing the

3

Wang S, Zhang S, Yao S. The proteinase related gene differential expression of human leukocyte caused by cardiopulmonary bypass. Anesthesiology 2004; 101: A208. (abstr).

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results of pre-clinical or early clinical trials of various MMPIs. This contrasts sharply with the current situation where it is difficult to find any reference to clinical uses of MMPIs for cancer. The reason for this is of course the expensive failures of multiple large-scale clinical trials, which have been well-documented and discussed in a number of articles [1-3]. Before completely abandoning the cancer setting, it is worth pointing out that there have been some glimmers of hope in the trials that were conducted and certainly strong indications that MMPs do play critical roles in tumor development and progression to metastatic disease. Kaposi’s Sarcoma The angiogenic tumor Kaposi’s sarcoma (KS) , which is most often associated with HIV infection but can also occur in some non-infected individuals, has been suggested as a suitable setting for trial of MMP inhibitors by the AIDS Malignancy Consortium (AMC), a National Cancer Institutesupported clinical trials group working with AIDS patients. The drug tested in these patients was the modified tetracycline CMT-3, which has potent activity particularly against the gelatinases MMP-2 and -9 but is less effective against collagenases [85]. In a phase I trial in KS, 18 patients were enrolled [86]. Of these 17 had recurrent disease following previous chemotherapy. There was an overall response rate of 44% with one complete and seven partial responses. Of particular interest, there were changes in the MMP-2 serum levels pre-and posttreatment, which were different in patients who responded versus those that did not. In responders the MMP-2 levels decreased by an average of 56 ng/ml whereas in nonresponders the level instead increased by an average of 300 ng/ml. Levels of the angiogenic factor VEGF showed a similar trend but the changes did not reach statistical significance. The promising data from this phase I trial led to another AMC-sponsored trial for phase II clinical testing of CMT-3 in 75 AIDS-related KS patients. While the trial has been completed, results have not yet been reported. Gastric Cancer Whereas all phase III clinical trials of various different MMPIs failed to meet their primary endpoints and were thus considered failures, there are some trials where the results suggest some efficacy in particular patient populations. One such trial was a phase III trial of the MMPI marimastat (British Biotech plc, Oxford, England) in 369 patients with gastric cancer [87]. The patients were randomized to receive either 25 mg marimastat twice a day, the dose found to be the maximum tolerated dose (MTD) from earlier clinical testing, or a placebo. The way in which patients were randomized to the two groups ensured balanced patient populations in each so that true comparisons could be made. Although the marimastat-treated group trended toward better survival, the result was not significant (p=0.07). The secondary endpoint of progression-free survival did yield a significant result in favor of marimastat (p =0.015). Since survival after 6 months was the primary endpoint, the lack of a significant difference between treated and untreated patients meant a failed trial. Nevertheless, the investigators reanalyzed the data, subgrouping patients with different clinical

Barbara Fingleton

parameters. This subgroup analysis indicated that in the 123 patients who had previously responded to chemotherapy, treatment with marimastat prolonged survival by 2.5 months (p = 0.045). In the 101 patients without metastasis, marimastat treatment offered a significant survival advantage (p =0.022). Furthermore, when looking at the entire patient population at a longer timepoint i.e after 1 year, the group treated with marimastat showed significantly enhanced survival (p = 0.024). Neither the subgroup analysis nor the survival after 1 year data should be interpreted to mean that actually the trial succeeded. In the case of the subgroup analysis, the careful balancing of patients between the treatment and placebo groups was no longer valid hence there is always the possibility that some other factor(s) related to characteristics of the patients in each group was responsible for the positive result. Since the trial was designed to examine effects on survival after 6 months, the number of patients accrued was appropriate for that endpoint and may not have been for longer timepoints. Nonetheless, these data are promising and clearly indicate an appropriate setting for any new trial of an MMPI in cancer patients. Renal Cell Carcinoma Cancer of the kidney is not as highly prevalent as cancer of the lung, breast or colon, however it is one of the cancers with the worst prognosis as there very few agents with any therapeutic efficacy in the majority of patients. The shark cartilage extract, Neovastat (Aeterna Zentaris Inc, Quebec, Canada), which has been promoted both for its MMPI and anti-VEGF activities has been targeted to renal carcinoma patients [88]. Results from phase II trials were extremely promising showing an apparent significant increase in survival. Unfortunately these results were not repeated in a larger 305 patient phase III trial in which overall survival was not different between Neovastat and placebo-treated patients4. As in the marimastat gastric cancer trial, a subgroup analysis did identify a specific patient group within the full cohort who responded well to Neovastat. These were healthier patients with clear cell histology and only one metastasis and their median survival time was increased from 12.6 months to 26.3 months by Neovastat. The results of another phase III trial of neovastat in non-small cell lung cancer has yet to be reported. Interestingly, for all markets except North America, neovastat has now been moved for marketing and distribution from the pharmaceutical company Aeterna to the Health and Nutrition division of its subsidiary Atrium Biotechnologies Inc.5 ARTHRITIS Arthritic disease can be divided into 2 main categories: osteoarthritis in which cartilage is destroyed in joints that have suffered chronic over-use or injury; and rheumatoid arthritis, an autoimmune disease where cartilage and bone destruction occurs in joints throughout the body. Osteoarthritis is a common development of ageing and as such is a huge

4

Biotech Tracker. Neovastat trial fails to meet primary endpoint [Web Page]. 25 September 2003; Available at www.bioportfolio.com/news/biotracker_186.htm. (Accessed 16th September 2005). 5 Aeterna Zentaris Inc. Neovastat Product Sheet [Web Page]. July 2005; Available at www.aeternazentaris.com (Accessed 16th September 2005).

MMPs as Clinical Targets

target market for pharmaceutical development. Rheumatoid arthritis, which is more prevalent in women than men, is also a large market with over two million sufferers in the US alone. As arthritis is a disease of excessive degradation of cartilage and bone, there is an extensive literature detailing the upregulation or induction of various MMPs and other proteinases in arthritic joints. Of course, therapeutic agents that could inhibit dissolution of the collagen matrix found in these tissues would be expected to be beneficial. For a comprehensive discussion of the MMPs in arthritis literature, readers are referred to a recent review by Burrage et al.[89]. Since arthritis is largely an inflammatory disease, the proteinases produced by inflammatory cells are significant contributors as are the proteinases whose expression is regulated by inflammatory molecules. In particular, the fibrillar collagenases MMP-1 and MMP-13 are thought to play significant roles. Evidence for this comes from studies of which MMPs are upregulated in arthritic joints and from animal models. An especially striking demonstration was a transgenic mouse overexpressing an active form of MMP-13 in cartilage that developed lesions very similar to those in human OA patients [90]. Hoffman-La Roche developed an inhibitor, Trocade, with selectivity for collagenase (MMP-1) and against the gelatinases (MMP-2 and MMP-9). Advanced clinical trials of this agent in RA patients were suspended in March 2000 and further development of the drug was terminated due to lack of efficacy and “an unfavorable risk-benefit profile”. Of note, the musculoskeletal side effects that plagued many of the other MMPIs were not seen with Trocade. This is despite it being an inhibitor of collagenase, inhibition of which is one of the hypothesized reasons for the MMPI side-effects. A more recent drug from Procter and Gamble, PG-530472, was tested in a phase II clinical trial of mild to moderate knee osteoarthritis6. This broad-spectrum drug effectively targets MMPs-2 and -9 as well as collagenases. The trial began in June 2002 with a scheduled enrollment of 340. The study is now reported as completed, however results have not yet been presented. A number of other agents have been reported as in clinical trials for OA e.g. CPA-926 (Kureha Chemical Industry, Tokyo, Japan) and ONO-4817 (ONO Pharmaceutical Co. Osaka, Japan) but there are no published reports of the results. Doxycycline has also been tested in a 30-month phase III clinical trial in patients with OA in one knee with the goal of determining whether drug treatment would decrease the severity or rate of progression of disease7. The results of this trial indicated that doxycycline treatment was associated with slower progression of narrowing of the joint spaces8 and reduced frequency of increases in knee pain 9. Other approaches to MMP reduction or inhibition have been tested in the laboratory setting and provide further sup-

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port that MMP activity is a critical component of arthritis. Inhibitors of histone deacetylases, which are potent inhibitors of gene transcription and which are in clinical development for a variety of diseases, have been shown to prevent inflammatory cytokine -mediated induction of MMPs-1 and -13 in human chondrocytes [91]. Chondroitin sulfate, a popular dietary supplement taken for joint health, has been demonstrated to inhibit synthesis of MMP-3 following interleukin-1beta exposure in chondrocytes from OA patients [92]. Additionally, when combined with glucosamine sulfate, chondroitin sulfate was effective at preventing MMP-9 induction and cartilage damage in adjuvant-induced arthritis in rats [93]. There is a large clinical trial due to be completed this year that is assessing whether use of glucoasmine and chondrotin sulfate truly benefits OA patients10. EYE DISEASE One of the first MMPIs to go into clinical trials was galardin, also called GM6001 or ilomastat. These early clinical trials of ilomastat/GM6001 were carried out by GlycoMed in patients with bacterial keratits-induced corneal ulceration [94]. Both safety and efficacy were demonstrated in these phase I/II trials, which were with topical application of the drug. GlycoMed, having merged with another company with different interests, no longer develops GM6001 and control of the drug reverted to its inventor. As one of the few MMPIs easily available to researchers through laboratory chemical companies, there has been continued testing of GM6001 in various animal models. Ilomastat, when administered subcutaneously to rabbit eyes that have undergone glaucoma surgery, was shown to have a similar effect on scar reduction as the gold standard treatment (mitomycin c). Impressively, this occurred without the conjuctivital epithelial cell damage that is a complication of mitomycin C treatment [95]. Thus far, these studies have been limited to animals but researchers are hoping to extend them to humans soon. In a related use, ilomastat delivered topically in eye drops can alleviate the extensive inflammation and neovascularization induced in eyes by exposure to mustard gas11. Skin damage, particularly blistering also induced by mustard gas exposure is also prevented by ilomastat treatment12. The development of ilomastat as a treatment agent for mustard gas exposures is the subject of a Cooperative Research and Development Agreement (CRADA) between the biotechnology company Quick-Med, Florida and the US army medical research institute for chemical defense. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD) is a term describing at least 2 pathologies, emphysema and chronic

6

Efficacy and safety of PG-530472 in the treatment of mild to moderate knee osteoarthritis [Web Page]. Available at www.clinicaltrials.gov. Identifier: NCT00041756. (Accessed 10th September 2005). 7 Doxycycline and OA progression. [Web Page]. Available at www.clinicaltrials.gov Identifier: NCT00000403. (Accessed 5th October, 2005). 8 Brandt KD, Mazzuca SA, Katz KP, Lane KA, the OA-Doxycycline Study Group. Doxycycline slows the rate of joint space narrowing in patients with knee osteoarthritis. Arth Rheum 2003; 48: 3652. (Abstr) 9 Brandt KD, Mazzuca SA, Katz KP, Lane KA, the OA-Doxycycline Study Group. The disease-modifying effect of doxycycline includes symptomatic benefit for patients with knee osteoarthritis. Arth Rheum 2003; 48: 3653. (abstr)

10 Glucosamine/Chondroitin arthritis intervention trial (GAIT). [Web Page]. Accessed at www.clinicaltrials.gov Identifier NCT00032890. Accessed 5th October, 2005. 11 Quick-Med Technologies Inc. Quick-Med Technologies announces successful clinical results for ilomastat [Web Page]. 22 April 2003; Available at www.quickmedtech. com/sub/news/news/news.220403.shtml. (Accessed 15th September 2005). 12 Quick-Med Technologies Inc. Quick-Med Technologies Inc announces a 2nd key clinical success for Ilomastat [Web Page].3rd June 2003; Available at www.quick medtech.com/sub/news/news/news.030603.shtml. (Accessed 15th September 2005).

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bronchitis, where patients develop breathing difficulties due to partial blockage of and/or damage to the bronchial tubes or alveoli. The principal cause of COPD is smoking and almost all sufferers are or have been long-term cigarette smokers. Involvement of MMPs in COPD has been proposed for some time, and significant evidence has accrued to suggest MMPs-1, -8, -9 and -12 are contributory to disease progression [96]. Bronchoalveolar lavage (BAL) fluid and/or sputum collected from COPD patients shows high levels of these proteinases in comparison to samples from healthy individuals, even those who are smokers [97-99]. MMP-12 activity has been suggested as a predominant proteolytic activity contributing to the pathogenesis of emphysema [100]. MMP-12, as its descriptive name, macrophage metalloelastase suggests, is highly expressed in macrophages [101]. As a potent elastase, MMP-12 can degrade one of the major pulmonary structural proteins, elastin. Fragments of elastin can be detected in the urine of patients with COPD and the levels correlate with severity of disease [102]. One of the strongest pieces of evidence implicating MMP-12 comes from studies in MMP-12-deficient mice. After exposure to cigarette smoke for 6 months, wildtype mice develop emphysema reminiscent of the human disease, however mice in which MMP-12 has been ablated are protected [101]. Since macrophage accumulation was attenuated in the lungs of the MMP-12-null mice compared to their wildtype counterparts, a macrophage chemoattractant protein was instilled into the lungs of mice of both genotypes resulting in equivalent numbers of lung-localized macrophages. In spite of this, the MMP12-null mice were still resistant to emphysema development. As further evidence of the central role of MMP12, a single instillation of recombinant human MMP-12 to mouse lungs was sufficient to induce a severe inflammatory reaction that culminated in significant macrophage accumulation out to 10 days [103]. Further evidence for the involvement of MMPs in COPD is catalogued in a recent review article [104]. Since there is strong data suggesting an involvement of MMPs in both the initial pathogenesis of emphysema and disease progression related to inflammation in COPD, it is unsurprising that MMP inhibition has been tested as a possible therapeutic modality. In guinea pigs exposed to cigarette smoke, the MMPI CP-471, 474 (Pfizer Inc, New York, NY) protected against emphysema development [105] while the broad-spectrum MMPI marimastat attenuated the inflammatory response invoked by instillation of recombinant MMP12 in mice [103]. To attempt to translate these findings to human patients, Arriva Pharmaceuticals (Alameda, CA) have licensed ilomastat and are developing it as a therapy for inflammatory respiratory disease. Thus far, the drug has shown efficacy in a mouse model of cigarette smoke-induced emphysema13. The approach taken by Arriva is to develop ilomastat as an inhaled drug to facilitate direct targeting to the tissue of interest. Such direct targeting allows significant dose reduction thus minimizing the chance of side-effects. Additionally, ilomastat displays poor solubility and bioavail-

13 Arriva Pharmaceuticals Inc. Arriva presents results from a preclinical study of a new inhaled drug, Ilomastat, that can cut tobacco smoke-related lung damage by 96% [Web Page]. September 2003; Available at www.arrivapharm.com/news-press.php?action= detail&newsID=13. (Accessed 15th September 2005).

Barbara Fingleton

ability so low doses in the lung are unlikely to yield significant systemic inhibitor levels. It is hoped that this approach will allow testing in a long-term study without the significant patient attrition rate that has been a feature of other MMPI trials. SKIN DISEASE MMPs have been identified as contributory factors in a range of skin lesions and wounds largely because of their production by inflammatory cells and their matrix-degrading ablilties. For these reasons, there have been several trials of various MMPIs in skin disease settings. The shark cartilage extract neovastat was tested as a monotherapy in a randomized phase I/II trial in patients with plaque psoriasis [106]. The highest dose of neovastat used (240mL/d), which was well-tolerated, resulted in statistically significant improvement in the psoriasis area and severity index (PASI) score. The further development of neovastat in this setting has apparently been discontinued by the drug maker Aeterna. Very recent results from a phase II study of the chemically modified tetracycline CMT-3 in patients with moderate to severe rosacea indicate a greater reduction in inflammatory lesion count in the CMT-3 vs placebo-treated patients [107]. An average 12.8 lesion reduction was seen in treated patients compared to an average 2.3 lesion increase in the control group. Additionally the effect was seen quite rapidly, with almost the entire reduction seen at 14 days. As a company targeting the dermatology market, CollaGenex are likely to expand these studies further. CONCLUDING REMARKS The MMP family of proteinases is responsible for the processing of numerous substrates. The best-known of these substrates are ECM proteins such as collagens and fibronectins. In fact, certain MMPs are the only extracellular proteases with the ability to hydrolyze fibrillar collagens. This ability of MMPs to remodel tissues through ECM proteolysis is the principal disease-associated function that has been considered in the majority of pathologies described in the preceding pages. Since there are many other MMP substrates, it is likely that the range of diseases in which MMPs truly play a role will expand as we understand more of the particular pathophysiologies involved. Nevertheless, we are still without specific inhibitors of these enzymes. This is partly due to the chronic settings in which MMPIs have been tested that exposed significant side-effect issues. Perhaps switching to acute scenarios will facilitate the approval of drugs that have already been developed. However, there also should be continued exploration of the nature of the sideeffects and how drugs that avoid them can be designed. One possibility is producing highly specific inhibitors of each MMP that could be used in various combinations if a more broad-spectrum approach is required. Since many of the MMP enzymes are structurally similar, such specific inhibitors have proven difficult to obtain. One strategy is to consider antibody-based inhibitors and this is an approach being tried. As an alternative to the development of MMPIs per se, other drugs already in clinical use that include downregulation of MMPs within their mechanism of action could be

MMPs as Clinical Targets

considered. Already tetracycline-derivatives such as doxycycline have been used in this way. Other drugs already in the clinic that may benefit patients with vascular disease by virtue of their MMP inhibitory activity are the statins [108,109]. There has been accumulating evidence to suggest that these hydroxymethylglutaryl-coenzyme A reductase inhibitors have effects on MMPs that are independent from the drugs’ impact on lipid metabolism [110]. Also a possibility for some diseases is the bisphosphonate type of drug. It has been realized for some time that various bisphosphonates can inhibit MMPs [111,112]. In this regard, zoledronic acid was tested recently in a mouse model of cervical carcinogenesis [113]. The investigators showed that the development of tumors in this model is MMP9-dependent using MMP9-deficient mice, and that the MMP-9 is produced by tumor-associated macrophages. Daily dosing with zoledronic acid targeted macrophage MMP-9 and prevented progression of premalignant lesions while in established tumors, it induced regression. Although the dose of zoledronic acid used in this study was significantly higher than what has been determined as safe and efficacious in humans, as a proof-ofconcept the results are very interesting and should be explored further.

Current Pharmaceutical Design, 2007, Vol. 13, No. 3

TNF

= Tumor necrosis factor

uPA

= Urokinase plasminogen activator

REFERENCES References 114-116 are related articles recently published in Current Pharmaceutical Design. [1] [2]

[3] [4]

[5] [6]

[7]

In conclusion, there is ample evidence that MMPs are involved in a multitude of human disease states and, from animal models at least, that MMP inhibition can effectively modulate disease progression. What are missing currently are safe, potent and tolerable drugs to test if the findings in animals can be translated to human patients.

[8]

ABBREVIATIONS

[11]

ADAM

[12]

= A disintegrin and metalloproteinase

[9]

[10]

ADAMTS = A disintegrin and metalloproteinase with thrombospondin AIDS

= Acquired immune deficiency syndrome

AMC

= AIDS malignancy consortium

ARDS

= Acute respiratory distress syndrome

COPD

= Chronic obstructive pulmonary disease

ECM

= Extracellular matrix

KS

= Kaposi’s sarcoma

LDL

= Low-density lipoprotein

MI

= Myocardial infarction

MMP

= Matrix metalloproteinase

MMPI

= Matrix metalloproteinase inhibitor (synthetic)

MTD

[13] [14]

[15]

[16]

[17]

[18]

= Maximum tolerated dose

MT-MMP = Membrane type matrix metalloproteinase OA

= Osteoarthritis

PMN

= Polymorphonuclear leukocyte

RA

= Rheumatoid arthritis

rtPA

= Recombinant tissue plasminogen activator

TIMP

= Tissue inhibitor of metalloproteinase

343

[19]

[20] [21]

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