The importance of estimating the therapeutic index in the development... matrix metalloproteinase inhibitors

Cardiovascular Research 69 (2006) 677 – 687
The importance of estimating the therapeutic index in the development of
matrix metalloproteinase inhibitors
J. Thomas Peterson *
Cardiovascular Biology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, United States
Received 20 July 2005; received in revised form 23 November 2005; accepted 26 November 2005
Time for primary review 29 days
At least 56 matrix metalloproteinase (MMP) inhibitors have been pursued as clinical candidates since the late 1970’s when the first
drug discovery program targeting this enzyme family began. Some of these clinical candidates were pursued for multiple indications.
However, the two primary indications that have been targeted are cancer (24 drugs) and anti-arthritis (27 drugs). Cardiovascular
disease was listed as an indication for 10 drugs. Forty-six MMP inhibitors have been discontinued, 7 remain in clinical development,
and only 1 (PeriostatR for periodontal disease) has been approved. Recently, negative phase II results were reported for the MMP
inhibitor PG-116800, which was being evaluated as a treatment for post-ischemic myocardial remodeling to prevent heart failure. One
major factor leading to the failure of PG-116800 and many of the other MMP inhibitors is the inadequate assessment of the
therapeutic index, the ratio of dose required for efficacy vs. that for toxicology. This review describes the dose-limiting side effect that
has hampered MMP inhibitor development (the musculoskeletal syndrome), cardiovascular clinical MMP inhibitor studies, a model of
the therapeutic index using marimastat, and progress towards more selective MMP inhibitors not limited by the musculoskeletal
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Matrix metalloproteinase inhibitor; MMP; Collagenase; Drug discovery; Drug development; Therapeutic index; Attrition; Heart failure
1. Introduction
Abnormal expression and activity of matrix metalloproteases (MMPs) has been linked to the pathological
processes underlying metastasis, angiogenesis, rheumatoid
arthritis and osteoarthritis as well as cardiovascular
disease. The potential utility of MMP inhibitors (MMPi)
in the treatment of pathological cardiovascular remodeling
has been underlined by preclinical observations that
degradation of the extracellular matrix is critical for
plaque destabilization [1– 4], aneurysm formation [5– 8],
stent restenosis [9– 11], post-ischemic myocardial remodeling [12 –14], and the development of systolic heart
* Tel.: +1 734 622 7189 (office); fax: +1 734 622 1480.
E-mail address: [email protected]
failure [15,16]. Of the 56 MMPi’s identified as clinical
candidates, only 10 have listed potential cardiovascular
indications (Table 1), only three of these compounds have
published cardiovascular clinical data. The lack of MMPi
cardiovascular clinical data can be attributed, in part, to
an initial historic focus on developing MMPi’s to treat
pathological: (1) degradation of type II collagen in
arthritis, and (2) degradation of extracellular matrix
proteins involved in angiogenesis and metastasis promoting tumor growth [17,18]. The notable failure to
demonstrate efficacy in arthritis and cancer clinical
studies, or in the case of BAY-12-9566 which appears
to facilitate tumor metastases in small cell lung cancer
[19], has delayed additional MMPi cardiovascular development. Early clinical studies with MMPi’s revealed a
severe adverse side-effect frequently referred to as the
musculoskeletal syndrome (MSS). The attempt of subse-
0008-6363/$ - see front matter D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
Table 1
Of the 56 known MMP inhibitor clinical candidates, only 10 compounds listed as having a cardiovascular indication
Product or compound name
Pfizer (Parke-Davis)
Systolic heart failure
Post-ischemic myocardial
Aortic aneurysm and arthritis.
British Biotech
Proctor and
Systolic heart failure
PREMIER Post-ischemic
myocardial remodeling
MT1-MMP inhibitors
3-D Pharmaceuticals
Nephrostat CMT
Restenosis and atherosclerosis.
Cardiac pressure-overload
hypertrophy and decompensation
leading to systolic heart failure
Aortic aneurysm
Washington University
Aortic aneurysm
PeriostatR Doxycycline
MIDAS Study Group
MIDAS Acute coronary syndrome
Of these 10, only three MMP inhibitors have published cardiovascular data: batimastat, PG-166800, and doxycycline.
quent MMPi clinical trials to avoid MSS coupled with an
inability to adequately assess the therapeutic index (i.e.,
the ratio between the dose required for efficacy vs.
toxicology), may have resulted in dose selection beneath
the minimal effective dose.
This review describes MSS, the tendonitis-like, doselimiting side-effect which has hampered efficacy assessment, the preclinical data supporting MMPi treatment of
plaque destabilization (MIDAS), stent restenosis (BRILLIANT), and post-ischemic myocardial remodeling (PREMIER). Because of the limited cardiovascular clinical data
available, human data from marimastat cancer trials is
related to an in vivo model of MMPi activity to show that
marimastat doses employed in Phase III studies may have
been below the minimal effective dose, thus explaining the
lack of efficacy with this MMPi. Finally, progress toward
the development of selective MMP inhibitors that does not
interact with the catalytic zinc ion of MMPs is presented.
2. The musculoskeletal syndrome
Ironically, a class of drugs developed to treat arthritis,
among other conditions, induces a tendonitis-like fibromylagia or musculoskeletal syndrome (MSS) in humans. In a
clinical study using marimastat, MSS events requiring dose
modification were not observed during the first 28 days of
dosing [20]. However, MSS occurred among a substantial
number of patients who continued in the long-term
continuation protocol. MSS events were dose related and
consisted of joint pain, stiffness, edema, skin discoloration,
and reduced mobility. The symptoms usually started in the
small joints of the hand, as well as the shoulder girdle,
typically on the dominant side. If dosing continues
unchanged, these symptoms spread to involve other joints
as well. Treatment with nonsteroidal anti-inflammatory
agents does not alleviate symptoms. A total of 10 / 30
patients in the long-term continuation protocol developed
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
MSS judged to be drug-related. Symptoms were severe
enough in 5 / 10 of the patients exhibiting MSS that the dose
was reduced. The time to onset of musculoskeletal toxicity
for the five patients with severe events varied from 56 days
(75 mg twice daily) to 199 days (25 mg daily). In another
marimastat study, patients with gastric cancer developed
arthralgia and joint stiffness. In addition, subcutaneous skin
thickening of the palmar surface of the hands, associated
with contracture of the digits was observed [21]. These
changes are described as resembling Dupuytren’s contracture, a thickening of the deep tissue that passes from the
palm into the fingers, and eventually results in the fingers
being pulled into the palm. The mean time to side-effect
onset was 45 days, but was to a large extent reversible
following the discontinuation of marimastat [21].
Other clinical studies have verified that MSS is dose and
time-related; involves joints in the hands, arms and
shoulders; is reversible following discontinuation of dosing;
and unresponsive to analgesics and NSAIDs [22,23]. One
group reported that MSS pain begins in the hands [20],
however, another group reported that pain started in the
shoulders and extends down to the hands which become
edematous [24]. The exact sequence of events may depend
on the drug used and the dosing regimen. The plasma drug
concentrations necessary to produce efficacy for batimastat,
marimastat, CGS-27023A and prinomastat also produced
MSS [25,26]. Clinical studies in which MMPi treatment was
not efficacious may have resulted because the therapeutic
index was not clearly defined, and too low a dose was
employed so as to avoid MSS. One study supporting this
hypothesis reported that drug treated cancer patients with
MSS showed a significant increase in survival time
compared to those which did not [27]. However, increased
survival in drug treated patients exhibiting more severe
MSS may have also resulted from an increased sensitivity to
an indirect (non-MMP) effect.
Several hypotheses based on a lack of selectivity have
been advanced to explain MSS. An early hypothesis was
that inhibition of MMP-1 (type 1 collagenase) activity
induced MSS. Both marimastat and RS-130830 are hydroxymate MMP inhibitors (C[ = O]NHOH), and both produce
MSS in humans. However, there is a wide separation in the
IC50 against MMP-1 for these compounds (0.15 vs. 223 nM,
respectively). The carboxylate inhibitors such as BAY 129566 and PG-116800 are even weaker inhibitors of MMP-1
(> 5000 nM and 1080 nM, respectively) and also produce
MSS in humans. The MSS observed following treatment
with MMP-1 sparing inhibitors indicates that inhibition of
this enzyme is not essential for this side-effect [28].
A more recent hypothesis is that inhibition of ‘‘sheddase’’
activity attributed to non-MMP ‘‘shallow pocket’’ metalloproteinases such as the adamalysins or tumor necrosis
factor alpha converting enzyme is the molecular mediator of
MSS [29]. The literature is unclear on this question. In a
recently described rodent model of MSS [30], MMPi’s that
are inactive against sheddases produces MSS like effect in
rats. This model provides both a screen to assess MSS
potential, and define the therapeutic index. MSS is
quantified in this model by scoring the presence and
magnitude of various clinical signs and histological changes
such as: compromised ability to rest on their hind feet; highstepping gait; reluctance or inability to move; and hind paw
swelling. Histological changes such as soft tissue and bony
changes, increased epiphyseal growth plate, synovial
hyperplasia and increased cellularity in the joint capsule
and extra capsular ligaments are also observed [30].
Marimastat treatment in rats produces a thickened growth
plate, and synovial deterioration compared to the vehicle
control. A moderate inflammatory cell infiltrate is also
present in this model [30]. These changes are dose and timedependent, and are reversible following the termination of
Identifying the mechanism of MSS has been complicated by the different functional role for a specific gene
across species. For example, mutation of MMP-2 causes
an arthritis-like syndrome in humans that involves carpal
and tarsal osteolysis, osteoporosis, palmar and plantar
nodules. This pathology is distinct from that of MMPi
induced MSS [31]. The deletion of the MMP-2 gene in
mice is not reported to result in similar joint defects.
Deletion of MMP-2 has a different consequence in humans
vs. mice.
Studies of MMP-9 and MMP-14 deficient mice suggest a
role for these MMPs in one or more events associated with
MSS (growth plate remodeling and endochondral bone
formation, release of angiogenic factors, neo-vascularization, apoptosis, and ossification. Deletion of the MMP-9
gene in mice produces growth plate enlargement, due to a
pronounced increase in the zone of chondrocyte maturation
and hypertrophy [32]. MMP-14 (membrane type-1 MMP)
gene deletion in mice produces joint defects including
endochondral ossification defects, osteopenia, fibrosis of
soft tissues and arthritis [33]. These changes are similar to
those observed following chronic marimistat treatment in
rats [30]. However, the soft tissue changes in both MMP-9
and MMP-14 knockout mice are characterized by fibrosis
rather than the fibroblast hyperplasia observed following
MMPi treatment. It is not clear what relevance the growth
plate changes in mice have to MSS in humans given that
epiphysis occurs at puberty while the average age of patients
in MMPi trials is above 40 years.
The most convincing evidence that MSS is not due to
MMP inhibition, per se, comes from experiments TIMP
gene expression experiments. NMR studies indicate that the
binding mode between TIMP homologs and MMPs are
similar to zinc-chelating MMPi’s. The N-terminal side-chain
(Thr2) of TIMP-1 57 and TIMP-2 [34] have both been
shown to extend into the S1Vpocket containing the catalytic
Zn2+ of MMP-3. The direct catalytic inhibitors of MMPs
also target the catalytic Zn2+ within the S1V pocket, and
presumably should share similar biological properties with
the TIMPs. Overexpression of TIMP-1 and TIMP-3 is
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
protective in mouse models of rheumatoid arthritis [35,36].
In one study, systemic treatment with significantly reduced
paw swelling and increased grip strength compared to
control groups. Radiographic assessment also demonstrated
a significant reduction of joint destruction in the AdTIMP-1
group, which was confirmed by histologic analyses showing
reduced formation of pannus and erosions [36]. Therefore,
MSS appears to be the result of non-selectivity (i.e., the
inhibition of some other metalloproteases), or the combined
inhibition of a combination of several critical MMPs.
3. MMP inhibitors and atherosclerotic plaque
MIDAS (Metalloproteinase Inhibition with submicrobial
doses of Doxycycline to prevent Acute coronary Syndromes), a 6 month prospective, randomized, double-blind
study tested whether subantimicrobial doses of doxycycline
hyclate (PeriostatR, 20 mg twice daily) reduced the
incidence plaque rupture as measured by sudden death,
myocardial infarction, and troponin-positive unstable angina
in 26 patients with existing coronary artery disease vs. 24
patients on placebo [37]. MIDAS is supported by histological studies of atherosclerotic lesions that have shown that
the plaque regions vulnerable to rupture are characterized by
inflammatory infiltrate, MMP upregulation, and collagen
degradation [2,3]. The mechanical forces at play on the
vulnerable regions of atherosclerotic plaque may exacerbate
the inflammatory response and proteolytic activity that
ultimately results in vessel occlusion and a clinic event.
Another rationale for evaluating the effect of Periostat in the
setting of coronary heart disease originates from a report
that periodontal inflammation is associated with an increased risk of heart disease and stroke [38]. The link
between periodontal and coronary disease was strengthened
in a subsequent study of 1147 men that revealed an
association between periodontal disease, a chronic Gramnegative infection, and atherosclerotic mediated thromboembolic events [39]. This association has been hypothesized
to result from an underlying inflammatory response trait
predisposing individuals to develop both periodontal disease
and atherosclerosis. In this scenario periodontal disease
produces endotoxins and cytokines that initiate and exacerbate atherogenesis and thromboembolic events [39]. The
relative risk for coronary heart disease, fatal coronary heart
disease, and stroke are up to 2.8 times greater for those with
periodontal disease vs. those without [39]. One potential
mechanism linking periodontal and coronary disease
involves periodontal bacteria gaining entry into the systemic
circulation, and bacteremia causing changes within the
arterial wall leading to atherosclerosis. A study of 50 human
specimens removed from carotid arteries revealed periodontal pathogens in all specimens of which 26% were
Porphyromonas gingivalis [40]. In a study using mice, oral
exposure P. gingivalis resulted in the spread of bacteria into
the bloodstream and ultimately the aorta, aortic inflamma-
tion ensued and accelerated atherosclerosis was evident by
17 weeks [41]. These results provide supporting evidence
that oral infection can accelerate atherosclerotic lesion
progression in the aorta.
Cytokines are involved in the destruction of periodontal
tissue, and can stimulate increased production of C-reactive
protein (CRP), an important marker of systemic inflammation. Patients with both coronary artery disease and
periodontal disease have been observed to have significantly
higher mean CRP levels (8-fold higher) compared to healthy
control patients with neither disease [42]. When the disease
group was provided periodontal treatment CRP levels
dropped 65% by 3 months post-treatment. This effect
persisted at 6 months post-treatment. In the MIDAS study,
50 patients were randomized to either a six-month subantimicrobial oral dose of Periostat (20 mg, bid) or placebo
control [37]. At enrollment, the two treatment arms had
similar demographic and clinical characteristics, including
age, sex, and frequency of hypertension, diabetes, smoking,
prior cardiac history, extent of coronary disease, presentation with acute myocardial infarction or unstable angina,
and need for a percutaneous coronary intervention. Periostat
significantly reduced CRP levels by 45.8% compared to
baseline values at the six-month follow-up period. Periostat
treatment was also associated with a 33.5% reduction in
interleukin-6 and a 50% reduction in MMP-9 activity
( p < 0.05). Low-dose Periostat was safe with no discontinuations due to treatment-related side effects. However, there
was no difference between the low-dose doxycycline and
placebo groups in the composite endpoint of cardiovascular
death, myocardial infarction, or troponin-positive unstable
angina. Brown et al. suggested that their study may have
been too short to permit adequate endpoint assessment.
Finally, Brown et al. hypothesized that positive feedback
loop may exist with systemic infection and inflammation
accelerating underlying atherothrombosis, inducing myocardial injury, resulting in IL 6 elevation which stimulates
hepatic CRP synthesis that in turn exacerbates atherothrombosis (in part through MMP upregulation) and thus
ultimately predisposing to plaque destabilization and additional myocardial injury. It is not clear what mechanism(s)
account for CRP and IL 6 reductions in MIDAS, or whether
continued Periostat treatment would have a significant and
substantial effect on cardiovascular morbidity and mortality.
An additional complication in the interpretation of the
MIDAS study is whether an adequate drug concentration
was achieved within the arterial wall. The predominant
mechanism by which Periostat decreases MMP activity does
not appear to be through direct inhibition, but rather an
indirect downregulation of MMPs. A comparable dose in
another study has been reported to produce human plasma
drug levels of 5– 10 AM [43]. In an in vitro system, 50 AM
doxycycline inhibited MMP-8 and MMP-13 degradation of
collagen type II by 64% and 77%, respectively, and had no
effect on MMP-1 [44]. The in vivo inhibition of the MMP
catalytic site may require substantially higher concentrations
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
of doxycycline than 50 AM, at least for the degradation of
fibrillar collagen (types I and III). Doxycycline appears to
decrease MMP activity by a variety of mechanisms:
reduction of enzyme stability [45], reduction of RNA
stability [46], and inhibition of transcription [47]. Some
cell types and tissues may be more sensitive to doxycycline
than others. For example, the dose of Periostat used to treat
periodontal disease (20 mg twice daily) may be effective
because of its reported ability to bind to the calcified
surfaces of tooth roots [48]. Tissue drug concentration can
be as much as 5-fold greater than that found in blood. The
gradual release of doxycycline from teeth in active form also
may contribute to increased exposure, and the prolonged
protection that has been observed following drug discontinuation during the post-treatment period. Therefore, it is
possible that gingival concentrations of Periostat are
sufficient to directly inhibit MMPs, and these tissue
concentrations were not achieved in the arterial wall of
patients dosed with Periostat in the MIDAS study.
4. MMP inhibitors and stent restenosis
BRILLIANT-EU (Batimastat antiRestenosis trIaL utiLizIng the BiodivYsio locAl drug delivery PC steNT), tested
whether an MMPi eluting stent (broad-spectrum inhibitor
batimastat, 0.2 mcg/mm2 of stent surface area) would inhibit
smooth muscle cell migration without interfering with the
re-endothelialization process [49]. The primary study
endpoint was a composite of major adverse cardiac events
(death/recurrent myocardial infarction (MI)/target lesion
revascularization) at 30 days. Secondary endpoints included
binary restenosis, subacute thrombosis at 30-day follow-up,
MACE at 6 and 12 months, and quantitative coronary
angiography at 6 months. Arterial injury, such as balloon
angioplasty activates vascular smooth muscle cells to
undergo a phenotypic change from a contractile state to a
synthetic one producing proteolytic enzymes that degrade
extracellular matrix proteins. Balloon injury induces the
expression of MMPs [50,51] as well as MMP activators
such as urokinase and tissue-type plasminogen activator
[52]. Increased MMP activity facilitates SMC migration
which, if too robust, can lead to restenosis [53] Batimastat
(30 mg/kg/day) treatment in a rat carotid artery balloon
injury model significantly inhibited intimal thickening after
arterial injury by decreasing SMC migration and proliferation [54]. BRILLIANT-EU study results showed that
batimastat-eluting stent was safe, but had no beneficial
effect on the rate of in-stent restenosis.
5. MMP inhibitors and post-ischemic myocardial
PREMIER (PREvention of MI Early Remodeling) trial
was performed to evaluate the effect of the MMPi, PG-
116800, reduced post-ischemic cardiac remodeling (i.e., left
ventricular dilation). MMP activity increases within hours of
ischemic injury in the heart, and changes in MMP and TIMP
expression continue for months post-MI [14,55]. Chronic
MMP upregulation has been proposed to mediate progressive cardiac remodeling and dilation that ultimately culminates in systolic heart failure. Inhibition of MMP activity by
gene deletion or MMPi treatment ameliorates cardiac
dilation [56 –58]. In the PREMEIR study, PG-116800 (also
referred to as PGE-530742 and PGE-7113313), was
administered at a dose of 200 mg bid, and the primary
endpoint was post-ischemic remodeling as measured by
increases in left ventricular end-diastolic volume (LVEDV).
Drug treatment was initiated within 24– 72 h following
diagnosis of myocardial ischemia, and the duration of
treatment was 90 days. LVEDV in the PG-116800 treated
group was not significantly different then placebo (LVEDVI
of 5.1 vs. 5.5 mL/m2, respectively, p = 0.42), and their was a
‘‘trend towards an increase in musculoskeletal events’’ [59].
The rationale for developing PG-116800 was that it was an
MMP-1 sparing compound that would avoid the MSS
syndrome. As noted earlier, RS-130830 has a similar MMP1 sparing profile to PG-116800, but was dropped from
development because of MSS. In a preclinical study using
infarcted pigs PGE-530742, a different formulation of PG116800, was administered at a dose of 10mg/kg (tid), and
reduced left ventricular dilation as measured by LVEDV by
approximately 31% compared to placebo control [60].
Assuming equivalent pharmacokinetics between pigs and
humans, the total clinical dose (2.5 – 3.0 mg/kg bid) was 3fold to 6-fold less than that found effective in pigs. The
lower human dose suggests a concern with triggering a side
effect, presumably MSS. Therefore, the PREMIER trial may
not have employed an adequate dose to test whether MMP
inhibition reduces post-ischemic remodeling in humans.
6. The therapeutic index of marimastat
Marimastat was chosen as a reference agent in this
review because it is the only MMPi with sufficient clinical
information available to illustrate the therapeutic index and
test the hypothesis that clinical dose selection may have
been below the minimal effective dose. Marimastat works
preclinically, improving median survival time and suppressing tumorigenesis in a variety of mouse cancer models [61 –
63]. Because MMPi’s are cytostatic rather than cytotoxic,
conventional measures of efficacy such as reduction in
tumor size could not be used to monitor drug activity. The
rate of increase in serum tumor markers was used as a
disease related biomarker strategy to guide dose selection
based on both preclinical [62] and clinical [22] studies. This
approach has been criticized because the rate of change in
serum tumor marker levels does not necessarily reflect
tumor regression [64]. As a consequence of these and other
issues, phase I MMPi cancer trials were often followed
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
Fig. 1. Representative uterine cross-sections harvested at day 4 postpartum and stained with picrosirius red to highlight fibrillar collagen. Little fibrillar collagen
is evident in uterus from vehicle treated rat on left. The preservation of collagen in uterus from marimastat treated rat is obvious.
immediately by phase II/III combination trials without the
benefit of efficacy information from smaller studies. In
addition to tumor markers, the use of circulating MMP
levels as a biomarker has met with mixed success in phase II
study. Analysis of circulating gelatinase levels by zymography is not predictive of cancer prognosis [65]. MMP-9
downregulation by col-3, a tetracycline derivative, does not
correlate with efficacy [66].
An animal model used in our laboratory to study in vivo
MMPi activity does provide an estimate of the concentration-effect relation of marimastat. The post-partum involuting rat uterus exhibits profound collagenolysis, a
phenomenon initially described over a half-century ago
[67,68]. This collagenolysis appears to be driven by matrix
metalloprotease (MMP) upregulation and activity. Approximately 60% to 80% of uterine collagen is degraded and lost
during the first 4 days postpartum in the rat [67,69]. MMP
13, or rat interstitial collagenase, has been proposed to
mediate collagenolysis in the involuting rat uterus [70]. This
phenomenon was used in our laboratory to screen MMPi
anti-collagenolytic activity for triaging heart failure compounds. The MMPi, marimastat, was used as a positive
control in this model. Rats were implanted with a
subcutaneous osmotic minipump to administer marimastat
because of the short half-life of this compound. Blood and
uterine samples were collected on day 21 (i.e., the day prior
to gestation) as a prepartum control. Samples from the other
groups were collected on day 4 postpartum. Two represen-
Fig. 2. Representative scanning electron micrographs from pre-partum control uterus, 4 day post-partum vehicle control, and 4 day post-partum marimastat
treated uterus. This figure illustrates the dramatic degradation of collagen that occurs with uterine involution, and the preservation of collagen content and
architecture with marimastat treatment.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
Fig. 3. Concentration – effect relation of marimastat on the inhibition of
collagen degradation using the involuting rat uterus in vivo efficacy model.
Rats were administered vehicle, 0.5, 1, 3.25, 6.5, or 9.75 mg/kg/day via an
Alzets osmotic minipump. Data show mean SEM (n = 8 per group).
tative uterine cross-sections harvested at day 4 postpartum
and stained with picrosirius red to highlight fibrillar
collagen (Fig. 1). The preservation of collagen in marimastat treated rat (right) compared to vehicle is obvious.
Scanning electron microscopy of uterine cross-sections
revealed that marimastat treatment did not alter the visual
appearance of collagen deposition in the uterus (Fig. 2).
Marimastat produced a dose-dependent inhibition of collagenolysis with a 56% inhibition of collagen degradation at
86 ng/mL (Fig. 3). Renkiewicz et al. in an experiment that
tested the 3 highest doses used in the experiment above
(3.25, 6.5, and 9.75 mg/kg/day) observed clinical symptoms and histological changes consistent with MSS in rat
[30]. A 3.25 mg/kg/day dose of marimastat reduced uterine
collagen degradation by 56% was shown to significantly
reduce left ventricular dilation in the MI-rat model [71].
The results from this animal model may also provide a
useful framework for modeling MMPi activity in other
diseases. There are significant caveats in extrapolating the
effect of marimastat in the involuting rat uterus to antitumor activity in humans given the difference in species,
tissue types, MMPs (as well as TIMPs), and substrates
involved. However, the concentration –effect relation of
marimastat against fibrillar collagen degradation in the rat
uterus, however, does provide a frame of reference for
understanding the clinical dose-selection of marimastat.
Table 2 provides a synopsis of all the clinical studies in
the literature for marimastat. In an initial phase I trial, the
highest dose tested (800 mg) generated a mean maximal
plasma concentration (Cmax) of 5.2 AM (2.0 Ag/mL), and
was reported as being well tolerated [72]. However, a
subsequent multiple dose tolerance study reported that
patients administered marimastat (100 mg, bid) for 2 weeks
showed an arthritis like syndrome (i.e., MSS) which
required the dose to be lowered [23]. Results from this
study indicated that a 50 mg bid dose with plasma drug
level less than or equal to 0.5 AM was tolerated. A
subsequent meta-analysis of tumor biomarker data indicated that a dose of at least 10 mg with a plasma drug level of
Table 2
Marimastat clinical studies summarizing data from 2978 patients
PK healthy males
PK healthy males
Lung cancer
Serum tumor markers
Gastric cancer
Historic control
Breast cancer
Gastric cancer
Colorectal cancer (Liver mets)
Breast cancer
Dose freq.
25, 50, 100,
200, 400, 800
25, 50, 100
50, 100, 200
5*., 10*.,
25*., 50.
25, 50
5*, 10*., 25*.,
50., 75.
200, 20
qd*, bid.
4% – 47%
qd*, bid.
37% (> 28 days)
33% (> 28 days)
Yes (CA 19/9)
55%, 36%
25, 50
5*, 10*., 25*
10, 100
5, 10
5, 10, 25
qd*, bid.
34% / 45%
7%, 7%, 12%
18% vs. 9%
35% vs. 2%
Yes (CEA)
Yes (CEA)
CA 19/9 and CEA represent surrogate biomarkers of anti-tumor efficacy. Frequency of dosing is marked in studies which employed both qd (once daily) and
bid (twice daily) dosing (* for qd and . for bid). If efficacy was based on a surrogate biomarker then the biomarker is identified in parenthesis. Studies with
equivocal findings are denoted by ‘‘???’’.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
0.1 AM was necessary for efficacy based on a significant
effect on surrogate biomarkers [22]. Therefore, marimastat
appeared to have at least a 5-fold therapeutic index, and
many of the phase III studies utilized a 10 mg bid dose
based on this data. Because MMP inhibitors are cytostatic
(cells are growth-arrested but viable) rather than cytotoxic
(cells are killed), conventional measures of efficacy such as
reduction in tumor size could not be used to monitor drug
activity. The rate of increase of serum tumor markers was
used as a disease related biomarker strategy to guide dose
selection [22]. This approach was criticized because the
rate of change in serum tumor marker levels does not
necessarily reflect tumor regression [64]. Four out of nine
phase II studies (Table 2) showed a beneficial effect based
on tumor biomarkers for the treatment of pancreatic and
colorectal cancer [20,22,73,74]. Phase III studies showed
that marimastat did not significantly improve survival for
neither pancreatic, colorectal, small cell lung cancer nor
glioblastoma [27,75 – 77]. Marimastat did show a significant effect on survival in patients with gastric cancer;
however, the increase in median survival was only 22 days
[78]. MSS was evident in all phase II and III efficacy
studies, and all these studies required some patients to go
to a lower dose, or discontinue dosing all together. Fig. 4
shows all published marimastat clinical studies reporting
plasma drug levels. The IC50 (concentration required for
50% inhibition) for marimastat against a panel of human
MMPs is shown on the far left (marimastat IC50: MMP-1
0.15nM, MMP-2 0.25nM, MMP-3 20 nM, MMP-7 1.19
nM, MMP-8 0.14 nM, MMP-9 0.68 nM, MMP-12 0.26
nM, MMP-13 0.7 nM, MMP-14 1.5 nM, MMP-15 1.01
nM, MMP-16 0.5 nM, MMP-24 0.8 nM) and the plasma
drug levels to the right. Dose(s) employed are shown above
each efficacy study, and the incidence of MSS below. MSS
has been reported to be dose-related within specific studies
[20,22]. A concentration-MSS response is not evident
across the studies shown in Fig. 4 for marimastat. Different
MSS scoring systems, duration of treatment, and potentially different patient populations are potential explanations for the lack of a between study marimastat plasma
concentration vs. MSS response relation. Another anomaly
in Fig. 4 is that the 10 mg bid dose in both breast cancer
studies fell far short of the desired 0.1 AM plasma
concentration target level. The 10 mg/kg dose in the other
cancer patient groups resulted in higher plasma drug levels.
Marimastat appears to have different pharmacokinetics in
breast cancer patients. The dashed line in Fig. 4 shows the
plasma concentration of marimastat which reduced collagen degradation by 56% in the rat uterus in vivo efficacy
model. Plasma levels in neither phase III shown in Fig. 4
exceeded this threshold, but both reported MSS. Although
it is not clear what level of in vivo collagenolytic inhibition
is required, Fig. 4 suggests that the assessment of
marimastat clinical efficacy was limited by dose, and this
has application to a recent phase II study of another MMPi,
Fig. 4. An illustration of the separation between the IC50 (i.e., concentration required for 50% inhibition) for marimastat across different MMPs (closed circles
on far left) and the plasma concentration required to produce a 56% inhibition of collagenolysis in a rat uterus model of in vivo efficacy (horizontal dashed
line). The plasma drug levels achieved in marimastat phase I (P I), phase II (P II) and phase III (P III) clinical studies shown to right of marimastat IC50’s. The
dose employed in each study is shown above the plasma drug level symbols. The percent incidence of MSS in each study is shown below the plasma drug level
symbols. The plasma drug level achieved in the 2 phase III studies were above the IC50’s of all the MMPs tested, but below the EC50 measured in the rat
efficacy model.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
7. Progress toward more selective MMP inhibitors
The search for selective MMP inhibitors has been driven
by a lack of understanding regarding the molecular
mechanism mediating MSS, the dose limiting side effect
produced by MMPi’s. The affinity of most MMPi’s
depends primarily upon two factors: a chelating moiety
that interacts with the catalytic zinc ion, and hydrophobic
extensions protruding from the catalytic site in the
hydrophobic S1V subsite, a deep pocket containing the
catalytic zinc ion [79]. The specificity of MMPs results
from the shape of the hydrophobic S1’ pocket. The S2’
subsite is a shallow pocket open to solvent with minimal
protein-inhibitor interactions. Drug design has focused on
utilizing S2V interactions to build scaffolds of MMPi’s to
enhance physicochemical and pharmacokinetic properties
without affecting MMP binding affinity. The S3’ subsite is
located on the periphery of the MMP active site, and drug
design around this site typically produces little gain in
inhibitor affinity. To date, MSS has appears to be intrinsic
to MMP inhibitors which chelate zinc. Recently, micromolar inhibitors have been described which occupy the S1V
pocket of MMP-13 that do not interact with catalytic zinc
[80]. Nanomolar pharmacophores have been described
which occupy the S1V pocket without interacting the
catalytic zinc based on crystal structure analysis [81]. In
addition, one of the MMP-13 inhibitors has 50% oral
bioavailability thus indicating that it may be suitable for in
vivo use [81].
[1] Lee E, Grodzinsky AJ, Libby P, Clinton SK, Lark MW, Lee RT.
Human vascular smooth muscle cell-monocyte interactions and
metalloproteinase secretion in culture. Arterioscler Thromb Vasc Biol
1995;15:2284 – 9.
[2] Orbe J, Fernandez L, Rodriguez JA, Rabago G, Belzunce M,
Monasterio A, et al. Different expression of MMPs/TIMP-1 in human
atherosclerotic lesions. Relation to plaque features and vascular bed.
Atherosclerosis 2003;170:269 – 76.
[3] Uzui H, Harpf A, Liu M, Doherty TM, Shukla A, Chai NN, et al.
Increased expression of membrane type 3-matrix metalloproteinase in
human atherosclerotic plaque — role of activated macrophages and
inflammatory cytokines. Circulation 2002;106:3024 – 30.
[4] Pickering JG, Ford CM, Tang B, Chow LH. Coordinated effects of
fibroblast growth factor-2 on expression of fibrillar collagens, matrix
metalloproteinases, and tissue inhibitors of matrix metalloproteinases
by human vascular smooth muscle cells — evidence for repressed
collagen production and activated degradative capacity. Arterioscler
Thromb Vasc Biol 1997;17:475 – 82.
[5] Wilson WRW, Schwalbe EC, Jones JL, Bell PRF, Thompson MM.
Matrix metalloproteinase 8 (neutrophil collagenase) in the pathogenesis of abdominal aortic aneurysm. Br J Surg 2005;92:828 – 33.
[6] Eskandari MK, Vijungco JD, Flores A, Borensztajn J, Shively V,
Pearce WH. Enhanced abdominal aortic aneurysm in TIMP-1deficient mice. J Surg Res 2005;123:289 – 93.
[7] Kadoglou NP, Liapis CD. Matrix metalloproteinases: contribution to
pathogenesis, diagnosis, surveillance and treatment of abdominal
aortic aneurysms. Curr Med Res Opin 2004;20:419 – 32.
[8] Knox JB, Sukhova GK, Whittemore AD, Libby P. Evidence for altered
balance between matrix metalloproteinases and their inhibitors in
human aortic diseases. Circulation 1997;95:205 – 12.
[9] Caldwell RA, Vyavahare N, Langan EM, Laberge M. Matrix metalloproteinase inhibitor within an absorbable coating for vascular
applications: delivery device characterization and the reduction of
smooth muscle cell proliferation and migration. J Biomed Mater Res
A 2003;67A:1 – 10.
[10] Li C, Cantor WJ, Nili N, Robinson R, Fenkell L, Le Tran Y, et
al. Arterial repair after stenting and the effects of GM6001, a
matrix metalloproteinase inhibitor. J Am Coll Cardiol 2002;39:
1852 – 8.
[11] Feldman LJ, Mazighi M, Scheuble A, Deux JF, De Benedetti E,
Badier-Commander C, et al. Differential expression of matrix metalloproteinases after stent implantation and balloon angioplasty in the
hypercholesterolemic rabbit. Circulation 2001;103:3117 – 22.
[12] Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE,
et al. Targeted deletion of matrix metalloproteinase-9 attenuates left
ventricular enlargement and collagen accumulation after experimental
myocardial infarction. J Clin Invest 2000;106:55 – 62.
[13] Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH,
Lopez-Anaya A, et al. Matrix metalloproteinase inhibition attenuates
early left ventricular enlargement after experimental myocardial
infarction in mice. Circulation 1999;99:3063 – 70.
[14] Lindsey ML. MMP induction and inhibition in myocardial infarction.
Heart Fail Rev 2004;9:7 – 19.
[15] Deschamps AM, Spinale FG. Matrix modulation and heart failure:
new concepts question old beliefs. Curr Opin Cardiol 2005;20:211 – 6.
[16] Lee RT. Matrix metalloproteinase inhibition and the prevention of
heart failure. Trends Cardiovasc Med 2001;11:202 – 5.
[17] Hodgson JA. Remodeling MMPIs. Biotechnology 1995;30:554 – 7.
[18] Beckett RP, Davidson AH, Drummond AH, Huxley P, Whittaker M.
Recent advances in matrix metalloproteinase inhibitor research. Drug
Discov Today 1996;1:16 – 26.
[19] Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A,
et al. Comparison of gemcitabine versus the matrix metalloproteinase
inhibitor BAY 12-9566 in patients with advanced or metastatic
adenocarcinoma of the pancreas: a phase III trial of the National
8. Summary
To date, only three MMPi’s have been assessed clinically
for cardiovascular indications: doxycycline for acute coronary syndrome, batimastat eluting stents for restenosis, and
PG-116800 for the prevention of post-ischemic left ventricular dilation. In all three studies, there was no significant
difference between the drug and non-drug treated groups.
MMP inhibitors, which are potent zinc chelators such as
batimastat and PG-116800, appear to induce the musculoskeletal syndrome, the major side-effect limiting doseselection. A preclinical study of PG-116800, which demonstrated efficacy, had 3- to 6-fold higher plasma levels than
that observed in the clinical study, and in the preclinical
study dosing was three times daily rather than twice daily
used for humans. Analysis of marimastat phase III data
indicates that the dose employed may have been too low
based on an in vivo rodent model of MMPi activity. The
advent of selective MMP-13 inhibitors which do not interact
with catalytic zinc represent a new MMPi pharmacophore.
If this new class of selective MMPi’s does not cause MSS,
then selective inhibitors against one of the approximately 26
other human MMPs may be developed if a compelling
rationale for a single MMP mediating one or more
cardiovascular diseases can be established.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
Cancer Institute of Canada Clinical Trials Group. J Clin Oncol
2003;21:3296 – 302.
Rosemurgy A, Harris J, Langleben A, Casper E, Goode S, Rasmussen
H. Marimastat in patients with advanced pancreatic cancer — a dosefinding study. Am J Clin Oncol Cancer Clin Trials 1999;22:247 – 52.
Tierney GM, Griffin NR, Stuart RC, Kasem H, Lynch KP, Lury JT, et
al. A pilot study of the safety and effects of the matrix metalloproteinase inhibitor marimastat in gastric cancer. Eur J Cancer
1999;35:563 – 8.
Nemunaitis J, Poole C, Primrose J, Rosemurgy A, Malfetano J, Brown
P, et al. Combined analysis of studies of the effects of the matrix
metalloproteinase inhibitor marimastat on serum tumor markers in
advanced cancer — selection of a biologically active and tolerable
dose for longer-term studies. Clin Cancer Res 1998;4:1101 – 9.
Wojtowiczpraga S, Torri J, Johnson M, Steen V, Marshall J, Ness E, et
al. Phase I trial of marimastat, a novel matrix metalloproteinase
inhibitor, administered orally to patients with advanced lung cancer. J
Clin Oncol 1998;16:2150 – 6.
Boasberg P, Eisenberg M, Harris J, Langleben A, Ahmann F, Roth B,
et al. Marimastat in patients with hormone refractory prostate concer: a
dose-finding study. Proc Am Soc Clin Oncol 1997;16:316A.
Drummond AH, Beckett P, Brown PD, Bone EA, Davidson HW,
Galloway A, et al. Preclinical and clinical studies of MMP inhibitors
in cancer. Ann NY Acad Sci 1999;878:236 – 70.
Hutchinson JW, Tierney GM, Parsons SL, Davis TRC. Dupuytren’s disease and frozen shoulder induced by treatment with a
matrix metalloproteinase inhibitor. J Bone Joint Surg Br 1998;
80B:907 – 8.
King J, Zhao J, Clingan P, Morris D. Randomised double blind
placebo control study of adjuvant treatment with the metalloproteinase
inhibitor, marimastat in patients with inoperable colorectal hepatic
metastases: significant survival advantage in patients with musculoskeletal side-effects. Anticancer Res 2003;23:639 – 45.
Whittaker M, Floyd CD, Brown P, Gearing AJH. Design and
therapeutic application of matrix metalloproteinase inhibitors. Chem
Rev 1999;99:2735 – 76.
Bird J, Montana G, Wills RE, Baxter AD, Owens DA. Chem Abstr
Renkiewicz R, Qiu LP, Lesch C, Sun X, Devalaraja R, Cody T, et al.
Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Arthritis Rheum
2003;48:1742 – 9.
Martignetti JA, Al Aqeel A, Al Sewairi W, Boumah CE, Kambouris
S, Al Mayouf S, et al. Mutation of the matrix metalloproteinase 2 gene
(MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat
Genet 2001;28:261 – 5.
Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, et
al. Mmp-9/gelatinase b is a key regulator of growth plate angiogenesis
and apoptosis of hypertrophic chondrocytes. Cell 1998;93:411 – 22.
Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov
SA, et al. MT1-MMP-deficient mice develop dwarfism, osteopenia,
arthritis, and connective tissue disease due to inadequate collagen
turnover. Cell 1999;99:81 – 92.
Fernandez-Catalan C, Bode W, Huber R, Turk D, Calvete JJ, Lichte
A, et al. Crystal structure of the complex formed by the membrane
type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase a receptor. EMBO J
1998;17:5238 – 48.
Schett G, Hayer S, Tohidast-Akrad M, Schmid BJ, Lang S, Turk B,
et al. Adenovirus-based overexpression of tissue inhibitor of
metalloproteinases 1 reduces tissue damage in the joints of tumor
necrosis factor alpha transgenic mice. Arthritis Rheum 2001;44:
2888 – 98.
van der Laan WH, Quax PHA, Seemayer CA, Huisman LGM,
Pieterman EJ, Grimbergen JM, et al. Cartilage degradation and
invasion by rheumatoid synovial fibroblasts is inhibited by gene
transfer of TIMP-1 and TIMP-3. Gene Ther 2003;10:234 – 42.
[37] Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM.
Clinical and biochemical results of the metalloproteinase inhibition
with subantimicrobial doses of doxycycline to prevent acute coronary
syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol
2004;24:733 – 8.
[38] Loesche WJ, Schork A, Terpenning MS, Chen YM, Dominguez BL,
Grossman N. Assessing the relationship between dental disease and
coronary heart disease in elderly vs veterans. J Am Dent Assoc
1998;129:301 – 11.
[39] Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal
disease and cardiovascular disease. J Periodontol 1996;67:1123 – 37.
[40] Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ.
Identification of periodontal pathogens in atheromatous plaques. J
Periodontol 2000;71:1554 – 60.
[41] Gibson FC, Hong C, Chou HH, Yumoto H, Chen JQ, Lien E, et al.
Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004;
109:2801 – 6.
[42] Genco RJ, Glurich I, Haraszthy VI. Overview of risk factors for
periodontal disease and implications for diabetes and cardiovascular
disease. Compend Contin Educ Dent Suppl 1998:S40 – 6.
[43] Modr Z, Dvorzhachek K, Schmidt O, Nechaskova A. Pharmacokinetics of doxycycline on its repeated oral administration. Antibiot
Khimiotr 1974;19:1063 – 7.
[44] Smith GN, Mickler EA, Hasty KA, Brandt KD. Specificity of
inhibition of matrix metalloproteinase activity by doxycycline —
relationship to structure of the enzyme. Arthritis Rheum 1999;42:
1140 – 6.
[45] Smith GN, Brandt KD, Hasty KA. Activation of recombinant human
neutrophil procollagenase in the presence of doxycycline results in
fragmentation of the enzyme and loss of enzyme activity. Arthritis
Rheum 1996;39:235 – 44.
[46] Liu J, Xiong WF, Baca-Regen L, Nagase H, Baxter BT. Mechanism of
inhibition of matrix metalloproteinase-2 expression by doxycycline in
human aortic smooth muscle cells. J Vasc Surg 2003;38:1376 – 83.
[47] Uitto VJ, Firth JD, Nip L, Golub LM. Doxycycline and chemically
modified tetracyclines inhibit gelatinase A (MMP-2) gene expression
in human skin keratinocytes. Ann NY Acad Sci 1994;732:140 – 51.
[48] Baker PJ, Evans RT, Coburn RA, Genco RJ. Tetracycline and its
derivatives strongly bind to and are released from the tooth surface in
active form. J Periodontol 1983;54:580 – 5.
[49] Gruberg L, De Scheerder I. BRILLIANT-EU: Batimastat (BB94)
Antirestenosis Trial Using the BiodivYsio Local Drug Delivery PCStent. New York’ L.L.C. Medscape; 2003.
[50] Southgate KM, Davies M, Booth RF, Newby AC. Involvement of
extracellular-matrix-degrading metalloproteinases in rabbit aortic
smooth-muscle cell proliferation. Biochem J 1992;288:93 – 9.
[51] Zempo N, Kenagy RD, Au YP, Bendeck M, Clowes MM, Reidy MA,
et al. Matrix metalloproteinases of vascular wall cells are increased in
balloon-injured rat carotid artery. J Vasc Surg 1994;20:209 – 17.
[52] Clowes AW, Clowes MM, Au YP, Reidy MA, Belin D. Smooth
muscle cells express urokinase during mitogenesis and tissue-type
plasminogen activator during migration in injured rat carotid artery.
Circ Res 1990;67:61 – 7.
[53] Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth
muscle cell migration and matrix metalloproteinase expression after
arterial injury in the rat. Circ Res 1994;75:539 – 45.
[54] Zempo N, Koyama N, Kenagy RD, Lea HJ, Clowes AW. Regulation
of vascular smooth muscle cell migration and proliferation in vitro and
in injured rat arteries by a synthetic matrix metalloproteinase inhibitor.
Arterioscler Thromb Vasc Biol 1996;16:28 – 33.
[55] Lindsey ML, Mann DL, Entman ML, Spinale FG. Extracellular matrix
remodeling following myocardial injury. Ann Med 2003;35:316 – 26.
[56] Jayasankar V, Woo YJ, Bish LT, Pirolli TJ, Berry MF, Burdick J, et al.
Inhibition of matrix metalloproteinase activity by TIMP-1 gene
transfer effectively treats ischemic cardiomyopathy. Circulation
2004;110:II180 – 6.
J.T. Peterson / Cardiovascular Research 69 (2006) 677 – 687
[57] Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J.
Early short-term treatment with doxycycline modulates postinfarction
left ventricular remodeling. Circulation 2003;108:1487 – 92.
[58] Romanic AM, Harrison SM, Bao WK, Burns-Kurtis CL, Pickering S,
Gu JL, et al. Myocardial protection from ischemia/reperfusion injury
by targeted deletion of matrix metalloproteinase-9. Cardiovasc Res
2002;54:549 – 58.
[59] SCRIP. Early setback for MMP inhibitors in heart remodeling. World
Pharmaceutical News Date. 2005.
[60] Yarbrough WM, Mukherjee R, Brinsa TA, Dowdy KB, Scott AA,
Escobar GP, et al. Matrix metalloproteinase inhibition modifies left
ventricular remodeling after myocardial infarction in pigs. J Thorac
Cardiovasc Surg 2003;125:602 – 10.
[61] Kimata M, Otani Y, Kubota T, Igarashi N, Yokoyama T, Wada N, et al.
Matrix metalloproteinase inhibitor, marimastat, decreases peritoneal
spread of gastric carcinoma in nude mice. Jpn J Cancer Res
2002;93:834 – 41.
[62] Watson SA, Morris TM, Collins HM, Bawden LJ, Hawkins K, Bone
EA. Inhibition of tumour growth by marimastat in a human xenograft
model of gastric cancer: relationship with levels of circulating CEA.
Br J Cancer 1999;81:19 – 23.
[63] Kimata D, Otani Y, Kubota T, Igarashi N, Yokoyama T, Wada N, et al.
[Antitumor effect of a matrix metalloproteinase inhibitor, TA-2516
(Marimastat), on a nude mouse model of intraperitoneal seeding of
stomach cancer]. Nippon Geka Gakkai Zasshi Journal of Japan
Surgical Society 1999;100:363.
[64] Gore M, A’Hern R, Stankiewicz M, Slevin M. Tumour marker levels
during marimastat therapy. Lancet 1996;348:263 – 4.
[65] Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001;93:
178 – 93.
[66] Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L,
et al. Matrix metalloproteinase inhibitor COL-3 in the treatment of
AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol 2002;20:153 – 9.
[67] Harkness RD, Moralee BE. The time-course and route of loss of
collagen from the rat’s uterus during post-partum involution. J Physiol
[68] Woessner JF, Brewer TH. Formation and breakdown of collagen and
elastin in the human uterus during pregnancy and post-partum
involution. Biochem J 1963;89:75 – 81.
[69] Morrione TG, Seifter S. Alteration in the collagen contrent of the
human uterus during pregnancy and post partum involution. J Exp
Med 1962;115:57 – 62.
[70] Jeffrey JJ, editor. Regulation of matrix accumulation. New York’
Academic Press; 1986.
[71] Schroeder RL, Olsen KF, Peterson JT, Haleen SJ. The broad
spectrum MMP inhibitor marimastat inhibited early left ventricular
dilation following coronary artery ligation in the rat. Circulation
[72] Millar AW, Brown PD, Moore J, Galloway WA, Cornish AG, Lenehan
TJ, et al. Results of single and repeat dose studies of the oral matrix
metalloproteinase inhibitor marimastat in healthy male volunteers. Br J
Clin Pharmacol 1998;45:21 – 6.
[73] Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JAC.
Marimastat as first-line therapy for patients with unresectable
pancreatic cancer: a randomized trial. J Clin Oncol 2001;19:3447 – 55.
[74] Primrose JN, Bleiberg H, Daniel F, Van Belle S, Mansi JL, Seymour
M, et al. Marimastat in recurrent colorectal cancer: exploratory
evaluation of biological activity by measurement of carcinoembryonic
antigen. Br J Cancer 1999;79:509 – 14.
[75] Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels
JAC. A double-blind placebo-controlled, randomised study comparing
gemcitabine and marimastat with gemcitabine and placebo as first line
therapy in patients with advanced pancreatic cancer. Br J Cancer
2002;87:161 – 7.
[76] Shepherd FA, Giaccone G, Seymour L, Debruyne C, Beziak A,
Hirsh V, et al. Prospective, randomized, double-blind, placebocontrolled trial of marimastat after response to first-line chemotherapy in patinets with small-cell lung cancer: a trial of the National
Cancer Institute of Canada-Clinical Trials Group and the European
Organisation for the Research and Treatment of Cancer. J Clin
Oncol 2002;20:4434 – 9.
[77] Phuphanich S, Levin VA, Yung WK, Forsyth P, Maestro R, Perry J. A
multicenter, randomized, double-blind, placebo-controlled (PB) trial
of marimastat (MT) in patients with glioblastoma multiforme or
gliosarcoma following completion of conventional first-line treatment.
Proc Am Soc Clin Oncol 2001;20:52.
[78] Bramhall SR, Hallissey MT, Whiting J, Scholefield J, Tierney G,
Stuart RC, et al. Marimastat as maintenance therapy for patients with
advanced gastric cancer: a randomised trial. Br J Cancer 2002;86:
1864 – 70.
[79] Skiles JW, Gonnella NC, Jeng AY. The design, structure, and
therapeutic application of matrix metalloproteinase inhibitors. Curr
Med Chem 2001;8:425 – 74.
[80] Chen JM, Nelson FC, Levin JI, Mobilio D, Moy FJ, Nilakantan R,
et al. Structure-based design of a novel, potent, and selective
inhibitor for MMP-13 utilizing NMR spectroscopy and computeraided molecular design. J Am Chem Soc 2000;122:9648 – 54.
[81] Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler
O, et al. Structural basis for the highly selective inhibition of MMP-13.
Chem Biol 2005;12:181 – 9.
[82] Quirt I, Bodurtha A, Lohmann R, Rusthoven J, Belanger K, Young
V, et al. Phase II study of marimastat (BB-2516) in malignant
melanoma — A clinical and tumor biopsy study of the National
Cancer Institute of Canada Clinical Trials Group. Invest New Drugs
2002;20:431 – 7.
[83] Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, Yung
WKA, et al. Phase II trial of temozolomide plus the matrix
metalloproteinase inhibitor, marimastat, in recurrent and progressive
glioblastoma multiforme. J Clin Oncol 2002;20:1383 – 8.
[84] Evans JD, Stark A, Johnson CD, Daniel F, Carmichael J, Buckels J,
et al. A phase II trial of marimastat in advanced pancreatic cancer.
Br J Cancer 2001;85:1865 – 70.
[85] Miller KD, Gradishar W, Schuchter L, Sparano JA, Cobleigh M,
Robert N, et al. A randomized phase II pilot trial of adjuvant
marimastat in patients with early-stage breast cancer. Ann Oncol
2002;13:1220 – 4.
[86] Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN,
Zucker S, et al. Randomized phase III trial of marimastat versus
placebo in patients with metastatic breast cancer who have responding
or stable disease after first-line chemotherapy: Eastern Cooperative
Oncology Group trial E2196. [erratum appears in J Clin Oncol. 23 (1)
(2005 Jan 1) 248]J Clin Oncol 2004;22:4683 – 90.
Explore flashcards