(Circulation. 1999;99:3292-3299.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A
From the Departments of Cardiovascular Biology (G.B., T.W., R.L., D.A., L.B., S.N., H.G., J.B., C.K., L.M., M.P., C.D.), Medicinal Chemistry (M.M., A.S., C.L., P.P.), and Laboratory Animal Resources (B.O.), Rhone-Poulenc Rorer, Collegeville, Pa, and Drug Metabolism (K.P.), Rhone-Poulenc Rorer, Dagenham, Essex, UK.
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Abstract |
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Background—Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis.
Methods and Results—RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg · kg-1 · d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98±0.09 versus 2.01±0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30±0.06 versus 2.52±0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16±0.05 versus 2.59±0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96±0.58 versus 0.67±0.09, P<0.05).
Conclusions—RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.
Key Words: angioplasty • restenosis • platelet-derived factors
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Introduction |
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Aclear understanding of the phenomenon of restenosis following angioplasty remains elusive. Restenosis following angioplasty occurs as a consequence of catheter-induced SMC migration, proliferation, matrix production, vasospasm, and remodeling,1 2 events driven by inappropriate growth factor ligand and receptor expression.1 2 Platelet-derived growth factor (PDGF) is one of several growth factors implicated in the restenotic process.3 PDGF ligands, established as potent mitogens, chemotactic agents, and inducers of matrix synthesis, produce effects by dimerization and activation of PDGF-receptor (PDGFr) subunits.4 Furthermore, as an essential co-stimulator in biologic responses of other cytokines/growth factors and mediators of the coagulation cascade,5 6 PDGF has an extensive biological scope of action.
In vivo, in small animal models of vascular injury, PDGF acts primarily to induce SMC migration7 8 and secondarily to promote intimal proliferation.8 9 Additionally, PDGFr activity, as determined by the state of receptor autophosphorylation, increases several days postinjury and persists for several weeks,10 11 providing a functional link between expression of PDGFr/ligand mRNA9 and proteins10 11 and potential biological influence on arterial stenosis. Results of immunocytochemical and in situ hybridization studies of human restenotic lesions12 13 reveal the presence of PDGF-A and -B ligands and PDGFßr from 6 to 56 days following PTCA and the correspondent absence of proteins and mRNA in nonlesioned sites. The expression of both ligands and receptor in regions of vascular repair provides evidence that autocrine/paracrine loops promoting PDGF-driven cellular activities, occur in human restenotic lesions.12 13
With evidence supporting a critical role for PDGF in arterial repair and restenosis following angioplasty, we investigated the ability of a selective inhibitor of the PDGFr-tyrosine kinase (TK) to block restenosis following angioplasty. We demonstrate that RPR101511A, a novel inhibitor of PDGFr-TK, abolishes PDGF-dependent cellular activities in vitro and when administered orally to the hypercholesterolemic adult minipig significantly reduces restenosis following angioplasty.
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Methods |
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In Vitro Assays
The effect of RPR101511A on PDGFr-TK was evaluated using the immunoprecipitated PDGFr cell-free ELISA assay14 ; the PDGFr was purified from human VSMC and the final ATP concentration was 20 µmol/L. Inhibition of PDGFr-dependent activities, including in situ receptor autophosphorylation, mitogenesis, cell number, and viability were as described.15 Exceptions were the use of human aortic VSMC (passage 4 to 6) and swine coronary VSMC. The latter were obtained by dispersal from slaughterhouse coronaries (passage 1 to 3). VSMC were growth-arrested for 24 hours, pretreated for 30 minutes with RPR101511A, and stimulated with a submaximal dose of PDGF-BB (10 ng/mL) or recombinant PDGF-AA (40 ng/mL). For western analysis, chemiluminescence was used to quantify antiphosphotyrosine and anti-PDGFr-detected proteins.
PDGFr-dependent chemotaxis was evaluated in a 96-well modified Boyden chamber (Neuroprobe, Inc) containing a collagen-coated polycarbonate membrane with cells preloaded with the fluorescent probe, calcein AM (5 µmol/L). PDGF (3 ng/mL) was placed in the lower chamber, and cell migration in the presence and absence of RPR101511A after 4 hours of incubation was determined by quantitation of fluorescence associated with the pores and underside of the membrane with Cytofluor II at excitation/emission wavelengths of 485/530.
To determine the effect of RPR101511A on other kinases, published protocols for CSF-1-receptor16 and EGF-receptor17 were followed. Protein kinase C (PKC) and protein kinase A (PKA) assays were conducted using commercially available kits according to the manufacturer's instructions (Sigma).
Measurement of coronary artery vasoreactivity followed published methods.18 Swine coronary artery rings were treated with RPR101511A, and steady-state tension produced by escalating concentrations of PDGF-BB, serotonin, or angiotensin II were recorded.
Restenosis Model
Thirty adult male Yucatan minipigs (Charles River Labs,
Wilmington, Mass), weighing 16 to 30 kg, were housed individually at
Rhone-Poulenc Rorer (RPR), Collegeville, Pa. Surgical and experimental
procedures were performed according to a protocol approved by the
Animal Care and Use Committee, RPR.
For lesion creation, pigs were anesthetized with Telazol (4.4 mg/kg, IM), intubated and ventilated with 2% isoflurane-oxygen. The medial ear vein and right external jugular vein were cannulated for administration of lactated Ringer's solution, heparin (3000 U bolus followed by 1000 U every 20 minutes), nitroglycerin (120 µg/min), and lidocaine (1 mg/min). An 8F introducer sheath was placed in the right carotid artery. Using fluoroscopic-guided assistance (Stenoscop II, GE Medical Systems), the LAD was overinflated (balloon/artery diameter=1.4, 3 inflations and endothelial denudation rub) with an angioplasty catheter (Intrepid, 7 ATM, Baxter Healthcare Laboratories) in an AR2-guide catheter (Scimed Boston Scientific Corporation). Pigs received aspirin (17 mg/kg BID) and an atherogenic diet (15% lard, 1.5% cholesterol mixed in swine minipig chow, Purina Mills, Inc) throughout the study.
One month following plaque creation, pigs underwent PTCA. Anesthesia, cannulations, and drug administrations were as described above. Plaque locus was determined from initial angiograms (first surgery). The balloon was expanded to achieve a 30% increase in lumen diameter. Following PTCA (three 20-second dilations), angiograms (postPTCA) were taken. External jugular vein access ports were implanted, subcutaneously, caudal to the scapula, to facilitate repeat blood withdrawal.
Pigs received RPR101511A (30 mg/kg) or vehicle by feeding tube twice daily for 28 days, beginning 2 hours before PTCA. A dosing suspension was prepared by mixing RPR101511A (Polytron tissumizer, Tekmar) with vehicle (0.5% methylcellulose [final]) and karo syrup, 50:50).
Twenty-eight days following PTCA, final angiograms (terminal-PTCA) were taken and pigs were euthanized with pentobarbital (78 mg/kg). The heart was removed and pressure perfusion fixed for 3 hours with 10% buffered formalin.
Histological Evaluation
Coronary arteries (LAD, circumflex) were cut into 4
mm sections, embedded in paraffin, and stained with Verhoeff's van
Giesen and Alcian Blue PAS (EPL Inc). A portion of each section was
deformalinized, frozen, sliced, and stained with oil red O for lipid
deposition. Four 5-µm side-by-side views from 5 levels within each
section were morphometrically and colorimetrically
evaluated with a Nikon microscope and attached to a drawing tube with
Sigma Scan software and/or an Olympus Vanox-S linked to ImagePro
computer analysis system (I-Cube). The circumference of
designated areas, injury index, and the number of internal elastic
lamina (IEL) fragments were also quantified. Histomophometric
analyses were performed by 3 scientists blinded to
treatment.
Angiographic Analysis
Lumen diameters on angiograms were determined by densitometric
analysis (Pharmacia LKB Biotechnology Inc). Eight measurements
were made spanning the lesion, and 3 measurements were made along the
dye-filled catheter. The location of the MLD, identified on the prePTCA
angiogram, was used to obtain lumen diameters at the corresponding
locus on post- and terminal-angiograms. The circumflex artery was
evaluated as the reference artery in a similar manner. Angiograms were
analyzed by 2 researchers blinded to treatment.
Plasma and Pharmacokinetic Analyses
Venous blood samples were obtained during PTCA surgery (day 0)
and on days 7, 14, 21, and 27 following angioplasty, 2 hours after the
morning dose. Plasma was analyzed for cholesterol
by the Hitachi 717 Chemistry Analyzer (Boehringer
Mannheim Corp). For quantitation of RPR101511A concentration, plasma
was diluted with acetonitrile and analyzed by HPLC
fluorescence assay using a LiChrospher RP18 with a linear range
of detection of 0.01 to 5 µg/mL.
Reagents
Cell culture media and human aortic VSMC were purchased from
Clonetics. Porcine PDGF-BB and recombinant human PDGF-AA were
products of R&D; RPR101511A was synthesized by Medicinal Chemistry,
RPR (Collegeville, Pa), according to patented
synthesis.19 Antibodies were purchased from
Transduction Laboratories and Genzyme.
Statistics
Results are presented as the mean±SEM. Statistical
significance was calculated using the paired t test for
means and the Student's t test assuming equal variance.
IC50 values were determined from linear
regression analysis of the percent inhibition from a minimum of
4 concentrations of RPR101511A.
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Results |
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In Vitro Effects of RPR101511A
RPR101511A (6,7dimethoxy-2-thiophen-3-yl-quinoxaline hydrochloride) (Figure 1
), is a potent
inhibitor of the human cell-free PDGFßr-TK with an
IC50 value of 106 nmol/L (Figure 2) and is selective for the PDGFßr-TK
compared with other tyrosine kinases (EGFr, CSF-1r) and
serine/threonine kinases (PKC, PKA) (Table 1). In a dose-related manner, RPR101511A
inhibited in situ PDGFßr-TK autophosphorylation
stimulated by PDGF (Figure 3A) and
PDGF-dependent mitogenesis in swine coronary SMC (SCSMC), the
relevant cell type in our in vivo restenosis model (Figure 3B). IC50 values (nmol/L) were 220±120
(n=3) and 254±90 (n=7) for the 2 activities, respectively. At
concentrations slightly higher than those required to inhibit SCSMC
mitogenesis, RPR101511A inhibited PDGFr
autophosphorylation, and PDGF-dependent chemotaxis and
mitogenesis in human aortic SMC (Table 2). In a 6-day cell growth assay, a
single application of RPR101511A retarded PDGF-dependent growth (Table 2). RPR101511A inhibited PDGF-AA-stimulated mitogenesis
suggesting that RPR101511A also blocked the PDGF
r-TK (Table 2).
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Initial signs of cytotoxicity were not evident until RPR101511A was added at a concentration which exceeded IC50 values by 100-fold (ie, 100 µmol/L), demonstrating that the inhibition of PDGF-dependent activities was not mediated by nonspecific VSMC cytotoxicity.
Inhibition of Angiographic Restenosis With
RPR101511A
To evaluate the effects of a selective PDGFr-TKI on
coronary artery restenosis, RPR101511A was administered
BID, beginning 2 hours before PTCA and continuing for 28 days. PrePTCA
MLD of the vehicle and RPR101511A-treated pigs were similar (Figure 4). Following successful dilation, the
MLD increased significantly and to the same extent in both groups.
Twenty-eight days following PTCA and oral treatment with vehicle or
RPR101511A, there was a significant decrease in the MLD of
vehicle-treated pigs but no angiographic change in the MLD of
RPR101511A-treated pigs. Thus, 54% (7 of 13) of the vehicle-treated
pigs exhibited >50% loss of gain compared with 23% (3 of 13) of
RPR101511A-treated pigs. This represents a 57% decrease in
restenotic rate. As shown by the equivalency of gain in the two
groups, by the similar angiographically determined balloon to artery
ratio in the 2 groups (Table 3) and by
the lack of change in the reference diameter of the 2 groups over time
(Table 3), the beneficial effect of RPR101511A on the MLD
following angioplasty was unlikely attributable to variable degrees
of injury or angiographic artifacts.
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Inhibition of Histological Intimal Hyperplasia
by RPR101511A
Figure 5 shows
representative examples of
histologically stained arterial lesions
from vehicle-treated (left) and RPR101511A-treated (right) pigs. Total
neointimal area, defined as the region between the lumen
and the IEL, is the complex lesion generated by the initial injury plus
the atherogenic diet albeit altered by PTCA compression and the
intimal growth which occurred during the 28 days following PTCA. Total
intimal area and total intimal/medial area (I/M) ratios of
sections displaying the minimal luminal area were significantly reduced
in tissues removed from pigs treated with RPR101511A compared with
vehicle (Figure 6). The average
histomorphometic minimal lumen area, lumen circumference, adventitial
area, artery area, and medial area were not significantly different
between RPR101511A-treated and control preparations.
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Total intimal area and I/M ratios of the entire lesion were reduced
with RPR101511A treatment (Table 4).
However, statistical significance was not achieved. Lumen area, medial
area, and artery areas were similar in the 2 groups (data not shown).
The extent of injury as estimated by the injury index and the number of
IEL fragments throughout the lesion were comparable in vehicle and
RPR101511A-treated pigs suggesting that the applied injury was similar
in the 2 groups. This is consistent with the angiographic data.
In addition, the EEL and IEL areas of the reference circumflex artery
untouched by the balloon catheter were comparable in the 2 groups (data
not shown).
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Vasoreactivity
Maximal isometric tension induced by three vasoconstrictor
agonists in porcine coronary artery rings and the effect of
RPR101511A on this vasoreactivity are given in Table 5. RPR101511A significantly inhibited
PDGF and angiotensin-mediated vasoconstriction but had no
effect on serotonin-induced vasoconstriction.
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RPR101511A Plasma Concentration
Pharmacokinetic studies conducted with RPR101511A in the Yucatan
minipig demonstrate a Tmax of 2 hours and a
T1/2 of 8 hours following oral administration. On
the basis of these results, plasma samples were collected 2 hours
postdosing every 7 days throughout the study. The mean plasma
concentration in RPR101511A-treated pigs ranged from 200 to 400 ng/mL
(0.65 to 1.29 µmol/L) during the study (Figure 7), concentrations in excess of those
used to inhibit PDGF-dependent mitogenesis of SCSMC in vitro (Figure 3
).
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Plasma Cholesterol
Because pigs were fed an atherogenic diet throughout the study,
plasma cholesterol increased from time of PTCA surgery to
termination. The increase in the control group was not significantly
different from the RPR101511A-treated group (mean change in total
cholesterol from day of PTCA to termination, control,
63±58 mg/dL; RPR101511A-treated,110±86 mg/dL). Additionally, the
relative density of oil red O staining for lipid (vehicle:RPR101511A,
mean±SEM) in the artery, (7781±990; 6988±764) plaque
(9167±1166;8213±1004), and the section with the MLD
(9841±1864;8704±1298) was similar in the 2 groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The oral efficacy of the selective PDGFr-TKI, RPR101511A, was evaluated in a porcine model of coronary artery restenosis following PTCA. This model shares similarities with human restenosis in several ways: PTCA was performed on a preestablished coronary lesion in the presence of elevated plasma cholesterol, surgical protocols were similar to those used clinically, lumen diameters were measured before and after PTCA and again 1 month later by angiography (Figure 4
) and at
termination, the restenotic lesion contained smooth muscle
cells, matrix, and lipids (Figure 5) comparable to human
restenotic lesions.20 21 This model differs
significantly from previously described models in which naïve
coronary arteries of normocholesterolemic pigs
were subjected to a single catheter-induced
injury.22 23 24
RPR101511A is a novel, low molecular weight inhibitor
(Figure 1) of PDGF-rTK autophosphorylation
(Figures 2 and 3A) and an inhibitor of
multiple PDGF-dependent activities of VSMC (Figure 3B, Table 2). Although PDGF has long been implicated in the development of
restenosis,1 the concordant expression of ligands
and the PDGFßr in human restenotic lesions has only recently
been demonstrated12 13 ; it reinforces the role of PDGF as
a critical player in the restenotic reparative process. In this
study, RPR101511A was used as a prototype selective
inhibitor of the PDGFr-TK to evaluate the role of
PDGF-dependent responses in a porcine model of coronary
restenosis. Our data demonstrate that oral administration of
RPR101511A prevented angiographically defined restenosis
(Figure 4). Pigs treated with RPR101511A exhibited no
angiographic loss of gain following PTCA whereas vehicle-treated
controls exhibited significant loss of gain (50%). Because both groups
received the same degree of angiographic dilation (Table 3,
Figure 4), the effect of RPR101511A was unlikely a consequence
of differences in applied injury.
Morphometrically, the total amount (ie, resulting from both the initial
injury and restenosis) of intimal hyperplasia in coronaries of
pigs receiving RPR101511A was significantly smaller (30%) than in
vehicle-treated pigs (Figure 6). Because we chose to evaluate
the effect of RPR101511A on PTCA-induced restenosis, ie, the
vascular response in the presence of a preexisting lesion, morphometric
quantitation of the intimal growth post PTCA was not possible and hence
only total intimal lesion data are presented. Thus, one
explanation for the modest inhibitory effect of RPR101511A
on intimal hyperplasia may relate to our inability to measure
selectively PTCA-induced restenotic intimal growth. Although
attempts were made to detect restenotic growth by differential
staining (eg, proteoaminoglycan sulfation with Alcian blue
PAS),25 this will be more meaningfully accomplished by the
use of intravascular ultrasound and will be included in subsequent
reports.
From in vitro characterization of RPR101511A as a potent
inhibitor of PDGF-dependent migration and proliferation in
VSMC (Table 2, Figure 3B) and from plasma levels of
RPR101511A (Figure 7) achieved in this study which exceeded the
in vitro IC50 values (Table 2), it is
reasonable to propose that inhibition of restenosis may occur
by inhibition of cellular activities initiated by PDGFr activation.
Although RPR101511A is without effect on EGFr-TK, CSF-1r-TK, and PKC
and PKA (Table 1), an effect on the TK receptors for
insulin–like growth factor-1 and fibroblast growth factor,
growth factors also implicated in restenosis,1
cannot be excluded. In addition, it is possible that RPR101511A exerted
a favorable vasodilatory effect on coronary arteries by
inhibition of vasoconstriction induced by PDGF or
angiotensin II (Table 5). However, the role of
vasoconstrictors in restenosis is unknown. RPR101511A reduced
restenosis independent of an effect on plasma
cholesterol and arterial wall accumulation of
lipid.
For results to be meaningful, according to the double injury model, the
applied injury both during plaque creation and at PTCA must be the same
in experimental and control animals. Because intravascular ultrasound
was not used, the extent of injury can only be determined indirectly.
This represents a limitation to this study. As with animal
stenosis models, an injury index is generated and as shown
here, this was similar in control and treatment groups (Table 4).
Another determinant of injury, one which would tend to
accumulate throughout the study, is the number of IEL fragments.
Our data show that the number of breaks in 4 contiguous lesion sections
were the same in both groups (Table 4). Angiographic data
provide balloon/artery ratios (Table 3) which indicate that
equal degrees of injury were applied to the LAD of both groups.
Currently, porcine models of (re)stenosis are considered to be the best approach for evaluating potential new therapies to modulate restenosis and to predict their success in man. In pig stenosis models, angiopeptin (a somatostatin analogue)22 and probucol, an antioxidant,23 have shown variable degrees of inhibition of intimal thickness, I/M ratio, and intimal area. They have similarly demonstrated some degree of clinical success in inhibition of restenosis.26 27 28 These results suggest that porcine models of (re)stenosis may be more predictable of the clinical outcomes using new treatment modalities than previous rat and rabbit models have been. Nonetheless, it is clear that there remains a void in the therapy for restenosis.
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Acknowledgments |
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The authors are grateful to Henry Sarau and Steve Young for their assistance with dosing; to Nonclinical Safety Assessment, Rhone-Poulenc Rorer for lipid analysis; and to Dr Lawrence Reilly of Process Chemistry for supplying RPR101511A. Histological assistance by Meggin McVey and David Rosolia were appreciated.
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Footnotes |
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Reprint requests to Glenda Bilder, PhD, Cardiovascular Biology, NW4, Rhone Poulenc Rorer, Collegeville, PA 19426.
T.W. is currently affiliated with Merck & Co, Westpoint, Pa; C.L. with Axys Pharmaceuticals, San Francisco, Calif; P.P. with Sepracor Inc, Marlborough, Mass; and C.D. with Lilly Research Labs, Indianapolis, Ind.
Received November 20, 1998; revision received March 18, 1999; accepted March 23, 1999.
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