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Matrix Metalloproteinases: Biologic Activity and Clinical Implications

From the Departments of Hematology/Oncology and Cell Biology, Vanderbilt University Medical Center, and the E. Bronson Ingram Cancer Center at Vanderbilt University, Nashville, TN.

Address reprint requests to Lynn M. Matrisian, PhD, Department of Cell Biology, Vanderbilt University Medical Center, T-2220, MCN, 1161 21st Ave South, Nashville, TN 37232; email lynn.matrisian@ mcmail.vanderbilt.edu.

ABSTRACT

ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

AFTER NEOPLASTIC transformation, cellular and molecular processes that are necessary for primary and metastatic tumor cell proliferation rapidly progress. Initial genetic alterations in gatekeeper genes result in the loss of normal growth control and the development of a benign tumor, with additional changes in caretaker genes being required for conversion to malignancy (see review in Kinzler and Vogelstein¹). After neoplastic transformation, tumor-host interactions promote coordinated molecular and cellular processes underlying a continuum of steps that define metastatic spread (Fig 1). Sequential, interrelated steps necessary for metastasis are similar for all tumor types and include tumor cell attachment (with proliferation initially being supported by nutrients from the surrounding microenvironment), neovascularization for further tumor growth, disruption of the basement membrane with subsequent invasion of malignant cells into the host stroma, intravasation into the blood or lymphatic circulation, survival and transport within the circulation, extravasation at distant sites, and growth within the new environment.² Considerable research has been directed toward outlining this cascade of events and defining the genetic events that underlie these processes as well as the effector genes, the protein products of which are responsible for the observed phenotypic changes.

View larger version (43K): [in this window] [in a new window]   Fig 1. Matrix metalloproteinases (MMPs) in tumor progression. The cellular changes that occur as a normal cell becomes a benign, malignant, and metastatic tumor are depicted. MMPs have been classically thought to contribute to the tissue destruction required for cells to invade, intravasate, extravasate, and migrate. More recent evidence suggests these enzymes can also play a role in the growth of benign and malignant tumors, angiogenesis, and the sustained growth of metastatic lesions.

Knowledge of processes and enzymes that are necessary for tumor progression has resulted in a dramatic expansion of potential targets for therapeutic intervention. At the same time has come the realization that controlling the cancer phenotype, rather than attempting to eradicate all affected cells, can provide significant benefits to the cancer patient. This review focuses on the current understanding of the biologic activities of MMPs in tumor progression and how this information has been translated into a new clinical treatment modality.

THE MMP FAMILY

The MMPs comprise a relatively large and ever-growing family. There are now more than 20 enzymes that are classified as MMPs. These enzymes have both a descriptive name (eg, interstitial collagenase, an enzyme found in the interstitial space, which degrades fibrillar collagens) and an MMP number. Although the numbering system recognizes up to MMP-24, the nomenclature does not accurately reflect the actual number of enzymes, because MMP-4, MMP-5, and MMP-6 have been eliminated as a result of duplication. Table 1 lists classification based on preferred substrate. It includes names and the primary substrates degraded by each enzyme. An alternative method of classifying these enzymes is based on structure. All MMPs have a similar domain structure, with a "pre" region to target for secretion, a "pro" region to maintain latency, and an active catalytic region that contains the zinc-binding active site.⁶ The majority of MMPs have additional domains, such as a hemopexin region or a fibronectin-like region. These additional domains are important in substrate recognition and in inhibitor binding. A subset of MMPs, known as membrane-type MMPs (MT-MMPs), also contains a transmembrane domain.⁷ Unlike the other members of the MMP family, MT-MMPs are not secreted but instead remain attached to cell surfaces. Although not all of the MT-MMPs are fully characterized, there is good evidence that one of their functions is to localize and activate secreted MMPs, particularly gelatinase A (MMP-2)^8,9 and collagenase-3.¹⁰

In addition to the MMPs, it is important to recognize the existence of a second family of proteins with metalloproteinase activity. These proteins are known as ADAMs (A Disintegrin And Metalloproteinase).¹⁴ As the name suggests, these proteins not only contain enzyme-like regions but also a disintegrin region that can mediate cell adhesion and fusion events.^15-17 Although the ADAMs themselves are a large family of approximately 30 members, only 16 are thought to have functional metalloproteinase activity. Of the endogenous MMP inhibitors, only TIMP-3 can efficiently inhibit the ADAM proteases.¹⁸ Because these proteins can be inhibited by many of the synthetic inhibitors developed for MMPs, they are of relevance when evaluating effects of synthetic MMP inhibitor (MMPI) administration.

MMPs and Malignancy
The role of MMPs in cancer was championed by Liotta et al⁵ in the early 1980s, when he identified proteolysis as one of the three essential steps of tumor invasion and identified a type IV collagenase as being involved in melanoma invasion and metastasis.⁵ Shortly after the cloning of the first MMPs,^19,20 it became clear that this activity was likely to be attributed to gelatinase A and/or gelatinase B. Although initially it was assumed that the tumor cell was the origin of the MMPs, there was growing evidence that host stromal cells respond to tumor cells by the induction of MMPs.²¹ The concept of stromal cell expression of MMPs was brought to the forefront by the identification of stromelysin-3 as a stromal metalloproteinase associated with breast cancer.²² Subsequent analysis of MMP expression by in situ hybridization revealed that stromal cell expression of MMPs is in general more common than tumor cell expression. Many MMPs are induced in connective tissue cells, including fibroblasts and inflammatory cells, as a response to the tumor. There are a few notable exceptions to this expression pattern. For example, matrilysin is commonly expressed in the epithelial component of adenocarcinomas, and many stromal MMPs are expressed in the malignant epithelium of tumors that have undergone an epithelial-to-mesenchymal transformation. In the case of gelatinase A, there is evidence that the mRNA is produced predominantly by stromal cells, but the protein is secreted and becomes bound to the invasive front of tumor cells.²³ Examples of the reported MMP expression in several common tumors are listed in Table 2.

There are some reports that suggest that expression of the MMPs or TIMPs may have diagnostic or prognostic value. For example, expression of stromelysin-3 in breast cancer has been associated with malignant disease only, and it is not expressed in normal breast tissue or benign fibroadenomas.³³ Stromelysin-3 expression was seen in all invasive breast carcinomas examined and, interestingly, in some in situ carcinomas where other factors indicated a high risk for the development of an invasive phenotype. Although several groups have identified an association between stromelysin-3 expression, lymph node metastasis, and/or shorter disease-free survival in patients with infiltrating ductal carcinoma of the breast, these findings require confirmation in larger studies.^30,34,36,81 A small study suggested that serum gelatinase A levels were higher in men with prostate cancer than in men with benign prostatic hypertrophy or normal prostates.⁸² Another group found that tissue expression of activated gelatinase A was associated with Gleason score, with the highest levels found in tumors with the highest Gleason score and in lymph node metastases.⁶⁴ Serum levels of gelatinase A were also found to be significantly higher in men with prostate cancer than in those with benign prostate hyperplasia or with no disease. Similarly, plasma TIMP-1 is associated with prostate cancer but not with benign prostate hyperplasia or normal prostate tissue.^61,83 In colon cancer samples, immunohistochemical detection of interstitial collagenase is associated with a poor prognosis independent of Dukes’ stage.⁸⁴ Matrilysin expression has also been suggested to be of prognostic value in colon and esophageal cancer. Reverse transcriptase polymerase chain reaction for matrilysin has been used to demonstrate that this enzyme can be a reliable marker of occult lymph node metastasis in colon cancer patients.⁸⁵ In a study of 100 patients with esophageal carcinoma, those individuals with tumors that demonstrated no matrilysin expression had a better disease-free and overall survival.⁸⁶ These observations are important because they not only link MMPs with aggressive malignant progression, but they also suggest that tumor-related expression of MMPs may provide important prognostic information that could help direct therapeutic recommendations, including the possibility of targeting inhibition of the MMP.

MMPs Play Multiple Roles in Tumor Progression: Evidence From Animal Models
The increased expression of MMPs in advanced tumors and the ability of these enzymes to degrade ECM barriers suggested a role for these enzymes in tumor metastasis. This hypothesis was well supported by a number of early studies that used experimental and spontaneous metastasis models and the TIMPs (see review in Chambers and Matrisian⁸⁷ ). For example, treatment of mice with recombinant TIMP-1 results in a significant decrease in the number of lung nodules after intravenous injection of B16-F10 melanoma cells.⁸⁸ A specific role for gelatinase A, gelatinase B, and MT1-MMP has been shown in increasing the ability of tumor cells to establish lung metastases after intravenous injection of bladder, fibrosarcoma, and lung cancer cells, respectively.^89-91 Gelatinase A, gelatinase B, and matrilysin have also been shown to contribute to the metastasis of cells to appropriate target organs from their primary sites in orthotopic models of bladder, fibrosarcoma, and colon cancer, respectively.^89,90,92 Because the experimental metastasis assay is dependent on extravasation of tumor cells from the bloodstream and the growth of detectable nodules, it was generally assumed that MMPs were required for the degradation of endothelial cell basement membrane to allow tumor cells to infiltrate the lung parenchyma. Interestingly, however, this view was challenged in studies that used intravital microscopy and quantitative analysis of extravasation. B16-F10 melanoma cells transfected with TIMP-1 gave increase to significantly fewer metastatic nodules than control cells⁹³ but were equally effective at exiting the bloodstream in the chick chorioallantoic membrane.⁹⁴ However, the ability of the extravasated cells to grow into visible tumor nodules was significantly altered by the presence of TIMP-1. These results suggested that MMPs act primarily to alter the extracellular environment and allow sustained growth in an ectopic site as opposed to having a specific role in allowing the cells to escape from the bloodstream into the extravascular space. Interestingly, the ability to exit the bloodstream seems to be a property of normal cells and is not dependent on malignant conversion, as normal embryonic fibroblasts have also been observed to effectively extravasate.⁹⁵

The role of MMPs in tumor cell invasion and intravasation, or entry of the tumor cells into the bloodstream, seems to be better established. TIMPs have been shown to inhibit tumor cell invasion of amnion or Matrigel (Becton Dickenson, Franklin Lakes, NJ) basement membranes in assays of in vitro invasion (see review in Chambers and Matrisian⁸⁷ ). In terms of roles for specific MMPs, matrilysin was observed to promote invasion of DU145 prostate cells into the diaphragm of nude mice.⁹⁶ More recently, an in vivo model of tumor cell intravasation was developed.⁹⁷ Using the chick chorioallantoic membrane, cells capable of invading the bloodstream and circulating to distant sites were quantitated. The intravasation of human epidermoid carcinoma cells was observed to be dependent on MMP activity and associated with the production of gelatinase B as well as requiring plasminogen activator activity. Thus although extravasation is a normal cellular function, the ability of tumor cells to cross the epithelial basement membrane, migrate through connective tissues, and enter blood vessels seems to be dependent on the elaboration of matrix-degrading proteases, including the MMPs.

The process of tumor cell metastasis is tightly coupled to tumor neovascularization, and MMPs have also been implicated in the process of angiogenesis. Based on recent work with MMP-null mice, gelatinase A and B may be in particular associated with neovascularization. For example, decreased angiogenesis was observed when B16-BL6 melanoma cells were seeded onto a millipore chamber and implanted into gelatinase A–null mice compared with wild-type controls.⁹⁸ The gelatinase B–null mice showed subtle defects in the growth of the long bones, which has been attributed to a delay in angiogenesis.⁹⁹ Specific effects of other MMPs on angiogenesis have not been directly tested in vivo, so it is unclear how many MMPs may contribute to tumor neovascularization. This is likely to be an important area for future research, as studies with natural and synthetic MMP inhibitors have underscored the importance of MMPs to the angiogenic process.¹⁰⁰

One of the primary effects of MMPs on tumor progression seems to relate to their ability to create an environment that is permissive for tumor growth. As discussed previously, the effect of TIMP on the establishment of distant metastases was related to its ability to inhibit the sustained growth of tumor cells in ectopic sites.⁹⁴ In addition to these effects on the establishment of secondary lesions, MMPs also seem to contribute to the establishment and growth of primary tumors in their normal environment. Specifically, human colon SW480 cells were more tumorigenic when they were injected into the cecum of nude mice if they were transfected with matrilysin,¹⁰¹ and there was higher tumorigenicity when MCF-7 human breast cells were injected subcutaneously into nude mice if they expressed stromelysin-3.¹⁰² The effect of stromelysin-3 on the establishment of breast cancers remains when the MMP is expressed by stromal cells as opposed to tumor cells. When MCF-7 cells were mixed with fibroblasts from wild-type or stromelysin-3–null mice, the stromelysin-3–expressing cells demonstrated much greater tumorigenicity.¹⁰³ Thus MMPs seem to be able to alter the extracellular environment in a way that encourages tumor cell establishment and growth.

The effect of MMPs on growth extends in some cases to benign as well as malignant tumors. The expression of interstitial collagenase in the skin of transgenic mice resulted in a significant increase in the number and onset of chemically induced benign papillomas.¹⁰⁴ Colon adenomas express matrilysin, and using matrilysin-null mice, Wilson et al¹⁰⁵ demonstrated that the number of adenomas was reduced in matrilysin-null mice that contained a mutation in the adenomatous polyposis coli gene that predisposed to multiple intestinal neoplasias. The synthetic MMP inhibitor batimastat (British Biotech PLC, Oxford, United Kingdom) had a similar effect,¹⁰⁶ which suggests that agents that are being developed to block the action of MMPs may be effective at inhibiting early stages of tumor progression and could be considered for use in a chemopreventive setting.

MMPIs

The important role of the MMPs in tumor progression and metastasis has prompted aggressive development of therapeutic agents that block enzyme activity in these processes. One approach has been the development of pseudopeptides that copy structural components of MMP substrates and thus act as competitive, reversible inhibitors. Another approach has used insight from x-ray crystallographic determination of three-dimensional structures of MMPs to generate nonpeptidic molecules that selectively bind to the zinc-binding site within the MMP. The resultant synthetic MMPIs can be either broad-spectrum or selective inhibitors. Broad-spectrum inhibitors effectively block multiple MMPs that may be involved in a wide range of processes that affect tumor growth, invasion, angiogenesis, and metastasis, whereas narrow-spectrum inhibitors have been designed to block the activity of selected MMPs that are closely associated with specific aspects of these processes. Table 3 lists five MMPIs and their inhibitory spectrum.

Similar reductions in primary tumor growth and the number and size of metastases have been demonstrated with other synthetic MMPIs. AG3340, a selective hydroxamic acid that was designed from information obtained through x-ray crystallographic structures of human MMPs, has been evaluated in several models that have different tumor/stromal interactions.^113,114 AG3340 initiated 3 weeks after implantation of the malignant glioma cell line decreased tumor size, resulted in less invasive tumors, and increased survival by more than two-fold. In a human lung cancer xenograft, treatment with AG3340 2 weeks after tumor implantation decreased the primary tumor weight, decreased mediastinal lymph node weight, and decreased systemic metastasis to kidney and bone. BAY 12-9566 is structurally distinct from other MMPIs. It is a butanoic acid derivative selectively targeted against gelatinase A and B and stromelysin-1. After removal of human MDA-MB-435 breast cancer tumors, BAY12-9566 resulted in inhibition of tumor regrowth, reduction in pulmonary metastasis, and decrease in volume of metastasis.¹¹⁵ Initiation of BAY12-9566 5 days after implantation of a human colon cancer cell line translated into a decrease in both tumor growth and metastasis.¹¹⁶

As noted previously, MMPs are involved in several steps that are critical to tumor progression and metastasis. There is now an emerging body of evidence that MMPIs can interfere with MMP function at many of these steps. DUC-26 prostate cells have an intrinsic invasive potential that correlates with expression of matrilysin. In a Matrigel invasion assay, migration of DUC-26 cells across a membrane was almost completely inhibited by batimastat.¹¹⁷ Similarly, tumor cell intravasation can be inhibited by synthetic MMPIs. Marimastat, a soluble equivalent of batimastat, reduced tumor cell intravasation by more than 90% in a chick chorioallantoic membrane assay.^97,118 MMPIs also inhibit angiogenesis. Quantification of angiogenesis by CD31 staining demonstrated that AG3340 can decrease the number of blood vessels in a human non–small-cell lung cancer model by up to 77% in a dose-dependent manner.¹¹⁹

Based on initial work done in a Lewis lung carcinoma model that combined an oral gelatinase inhibitor (CT1746) with cyclophosphamide to demonstrate greater tumor growth delay and reduction in pulmonary metastases than with either agent alone,¹²⁰ a great deal of work has been done to develop strategies that integrate MMPIs with cytotoxic chemotherapy. In a murine B16-F10 melanoma model insensitive to single-agent carboplatin, the combination of AG3340 and carboplatin decreased the formation of lung metastases by 70%, whereas AG3340 decreased this by 33% when used alone.¹²¹ Similarly, AG3340 in combination with paclitaxel decreased metastatic lesions by 83%, as compared with 50% for paclitaxel alone. The issue of concurrent versus sequential administration of synthetic MMPIs with cytotoxic agents in early-stage tumors has also been addressed.¹²² Median survival after implantation of human ovarian xenografts in nude mice was extended from 7 to 23 weeks in mice treated sequentially with cisplatin followed by batimastat, whereas survival was 11 and 18 weeks for single-agent treatments with batimastat and cisplatin, respectively. The most dramatic effect was seen in the group given concurrent treatment with cisplatin and batimastat: all mice were alive and tumor-free at the termination of the experiment at 28 weeks.

Clinical Data on MMPIs
The initial evaluation of most chemotherapeutic agents involves successive dose escalation to identify the maximum-tolerated dose and to describe dose-limiting toxicities. This approach assumes a dose-dependent cytotoxic effect using an intermittent drug administration schedule. In contrast, because of their noncytotoxic effects on the tumor, phase I studies with MMPIs have sought to establish tolerable doses of drug, suitable for protracted administration, that produce serum levels that exceed the inhibitory concentration of targeted MMPs without causing unacceptable normal tissue toxicity. A second formidable challenge faced in the clinical development of MMPIs has been the quantification of antitumor effect. Single-agent phase II clinical trials of new anticancer agents usually have objective response rate as their primary end point. Although preclinical models have demonstrated the impact that MMPIs can have on delaying growth of the primary tumor, decreasing the number and volume of metastatic lesions, prolonging time to tumor progression or recurrence, and increasing life span, the primary impact of MMPIs has not been substantial regression of large primary tumors. Given the limitations of secondary end points of response, the development of MMPIs has proceeded rapidly to phase III trial design with the end point of survival.

Batimastat was the first synthetic MMPI to enter human clinical trials. Poor solubility limited oral administration. Thus phase I and phase I/II trials^123,124 involved intraperitoneal and intrapleural administration to patients with cytology-proven malignant ascites and malignant pleural effusions. With this mode of administration, the drug was found to behave as a depot, resulting in sustained plasma concentrations. Common side effects included nausea, fatigue, low-grade fevers, abdominal pain in the case of intraperitoneal administration, asymptomatic elevation of hepatic enzymes, and pain at the injection site with intrapleural treatment.

Phase I trials of the orally bioavailable MMPIs have not only determined optimal biologic doses for further study but have also defined unique dose and time-dependent side-effect profiles. Hydroxamic acid derivatives that are undergoing clinical trials include marimastat and AG3340. The two agents differ in selectivity: marimastat is a broad-spectrum inhibitor, whereas AG3340 targets inhibition of gelatinase A and B, collagenase-3, and stromelysin-1. Phase I trials with marimastat in patients with advanced malignancies^125-132 identified a tolerable dose range and determined the main side effects to be fatigue and cumulative inflammatory polyarthritis that is reversible on discontinuation of treatment. Similarly, AG3340 causes time- and dose-dependent musculoskeletal pain that begins in the shoulders, hands, and knees but is reversible with treatment rest and subsequent dose reduction.¹³³ In patients with a variety of advanced malignancies, low doses of AG3340 were associated with milder and more delayed toxicities as compared with higher doses. Importantly, low-dose AG3340 yielded sustained plasma concentrations that were similar to those at which selective MMP inhibition and antitumor effect were observed in murine xenograft models. BAY12-9566 is structurally distinct from other MMPIs. It is a butanoic acid analog that is highly protein-bound and has essentially no action on interstitial collagenase. These features may account for its selectivity as well as its different side-effect profile. Phase I studies in patients with advanced solid tumors^134-137 reported no musculoskeletal toxicity but rather asymptomatic elevation in hepatic enzymes and thrombocytopenia, particularly in patients with decreased hepatic and hematopoietic reserve. Although there are little data available about CGS27023A, a phase I trial of this broad-spectrum MMPI has reported dose-limiting toxicities to be arthralgias, myalgias, and a self-limited maculopapular rash.¹³⁸

Some insight into the potential therapeutic activity of MMPIs is available from phase I studies. In a phase I trial of intrapleurally administered batimastat in patients with malignant pleural effusions, the number of therapeutic thoracentesis performed decreased from 43 over the 3 months that preceded treatment to 14 in the 3 months after batimastat administration in a subset of 12 patients who survived at least 3 months after initiation of treatment.¹³⁹ Overall, seven (44%) of 16 assessable patients required no further pleural aspirations after initiation of batimastat until death/last follow-up. Although encouraging, the small number of patients treated over a range of doses in this phase I trial preclude any firm conclusions about the therapeutic effectiveness of batimastat in this setting. In addition, the development of orally bioavailable MMPIs, for at least the time being, has supplanted batimastat in clinical trials.

Marimastat was the first orally bioavailable MMPI to enter clinical testing. Most of the phase I trials performed with this agent were disease-specific and were performed in patients with elevated and increasing serum tumor markers. Phase I/II trials were conducted in patients with pancreatic,^128,129 colorectal,^140,141 ovarian,^130,142 and hormone-refractory prostate cancer.^131,132 Assessment of drug effect included evaluation of the change in the rate of increase of serum tumor markers, including CA 19-9, carcinoembryonic antigen, CA-125, and prostate-specific antigen, from the period immediately preceding treatment to the period during treatment with marimastat. Although a combined analysis of the results from six trials identified an association between a decrease in the rate of increase of serum tumor markers and survival, the authors acknowledge the limitations of a "responder analysis" and the fact that this does not necessarily equate with beneficial drug effect.¹⁴³ Such a relationship can only be determined through phase III trials. Attempts to look at other surrogate markers that are more specific to the activity of the MMPIs have been disappointing. Zymographic analysis of serum proenzyme and activated forms of gelatinase A and B did not reveal any consistent patterns of change in MMP levels or degree of activation during treatment with marimastat.¹²⁵ Clinical efficacy data are not available from trials using AG3340. In advanced solid tumors, BAY12-9566 led to stable disease for at least 4 months in 40% of patients treated on one phase I study,¹³⁶ whereas a separate study reported on prolonged stable disease lasting for at least 6 months in four of 11 patients.¹³⁷ In evaluating the molecular effect of the MMPIs on plasma levels of angiogenic growth factors, however, BAY12-9566 had no demonstrable impact on vascular endothelial growth factor or basic fibroblast growth factor.¹³⁴

The results of two phase III trials have been reported to date. The first compared marimastat to gemcitabine in more than 400 patients with unresectable pancreatic cancer. In this trial, which was designed to detect a 16% or greater reduction in mortality, marimastat did not demonstrate therapeutic superiority over gemcitabine.^144,145 The second trial evaluated marimastat against placebo in 369 patients with inoperable gastric cancer who had received no more than one prior chemotherapy regimen. Although progression-free survival was improved in the marimastat group, no improvement was detected in the primary end point of the trial, overall survival. Subset analysis suggested an improvement in survival in patients without distant metastases at the time of enrollment, and there is a suggestion that long-term survival may be favorably affected by marimastat. Further details and follow-up on this study are awaited.¹⁴⁶

Safe administration of MMPIs alone, combined with preclinical data suggesting that an MMPI may potentiate the effects of chemotherapy, prompted phase I trials to examine the safety of concomitant treatment. Marimastat,^147-149 AG3340,¹⁵⁰ and BAY 12-9566¹⁵¹ have each been successfully combined with chemotherapy regimens that are commonly used in the treatment of lung, colon, prostate, pancreatic, and breast cancer. Each MMPI has been combined with the full dose of the cytotoxic agent/agents appropriate for the disease process without a significant change in toxicity for either the chemotherapy regimen or MMPI. These studies serve as the background for concomitant administration of agents, which is one of the phase III strategies being pursued.

Three different strategies have been used in phase III trials of MMPIs (Fig 2). The first strategy involves direct comparison of the MMPI with standard chemotherapy. The second strategy is concomitant administration of the MMPI with chemotherapy compared with chemotherapy alone. The third strategy directly compares an MMPI with placebo in patients with low-volume disease or no evidence of disease after front-line therapy. A summary of phase III trials performed to date is included in Table 4.

View larger version (31K): [in this window] [in a new window]   Fig 2. Clinical strategies with MMPIs.

In conclusion, proteolysis by the MMPs is clearly linked to tumor progression. As knowledge grows regarding the intricate, multifaceted interactions between a tumor and its microenvironment, it will become important to consider the contribution of MMPs in the context of other proteases. For example, there is significant evidence that the serine protease urokinase plasminogen activator/ urokinase plasminogen activator receptor/plasminogen network and the cysteine proteases cathepsin B and L are also involved in this process.^152,153 Preclinical studies indicate that combining a serine protease inhibitor with an MMPI augments inhibition of invasion, which suggests that targeting multiple proteases may be an effective strategy for blocking tumor growth and progression.¹⁵⁴ At present, agents that inhibit the MMPs alone are farthest along in development and have reached phase III clinical trials. These trials will provide us with important data in regard to proof of biologic activity and the clinical relevance of the MMPs. A number of challenges still remain. First, current methods of analysis have yet to demonstrate that MMPIs inhibit the activity of active MMPs that are associated with tumor growth and metastasis on a cellular level. The development of in situ assays to detect activity could not only help prove that synthetic inhibitors inhibit active MMPs, but could potentially help direct therapy by identifying a given tumor’s unique expression of active MMPs. Second, there is still much work to be done on further characterization of tumor and stromal expression of MMPs in individual cancers and characterization of their roles with regard to tumor behavior and prognosis. Third, we need to determine the relative merits of a therapeutic strategy that targets broad versus selective MMP inhibition. Fourth, although the results of the initial phase III trials evaluating MMPIs are just becoming available, it is possible that the full effect of this therapeutic approach may not be appreciated until it is tested in the adjuvant setting. Finally, we need to learn how the inhibition of MMPs can be most effectively integrated into current, and future, cancer therapies. In the long run, targeting processes that are involved in tumor growth and progression may fundamentally change the way in which we approach treatment of patients with cancer and convert this rapidly lethal disease into a more chronic—and survivable—ailment.

NOTES ADDED IN PROOF

Since the manuscript was submitted, Bayer Corp has suspended all clinical trials of its MMPI BAY 12-9566. Additional preclinical models are currently being evaluated.

British Biotech PLC has released results of its third phase III trial. In advanced pancreatic cancer, Marimastat in combination with gemcitabine offered no survival advantage over gemcitabine plus placebo.

ACKNOWLEDGMENTS

Supported by grants from E. Bronson Ingram Charitable Fund (M.L.R.), National Institutes of Health (grants no. NIH-RO1 CA46843 and CA60867; L.M.M.), and Vanderbilt Cancer Center (L.M.M.).

We acknowledge personal communications with British Biotech, Agouron, Bayer, and Novartis in creating Tables 3 and 4. We also acknowledge the contributions of Tracy Vargo-Gogola, Becky Wagenaar, Permila Harrell, and Mark Gustavson to Table 2.

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Submitted May 5, 1999; accepted November 3, 1999.

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