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Published online before print February 28, 2007, 10.1148/radiol.2431050658
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(Radiology 2007;243:105-111.)
© RSNA, 2007

Experimental Studies

MR Monitoring of Cyclooxygenase-2 Inhibition of Angiogenesis in a Human Breast Cancer Model in Rats1

Laure S. Fournier, MD, Viktor Novikov, MD, Vincenzo Lucidi, MD, Yanjun Fu, PhD, Theodore Miller, MD, Eugenia Floyd, DVM, David M. Shames, MD and Robert C. Brasch, MD

1 From the Center for Pharmaceutical and Molecular Imaging, University of California, San Francisco, San Francisco, Calif. Received April 20, 2005; revision requested June 15; final revision received February 28, 2006; accepted April 6; final version accepted August 1. Supported in part by National Institutes of Health grant no. RO1 CA82923. L.S.F. supported by a postdoctoral stipend from the Association pour la Recherche sur le Cancer (2001) and the Philippe Foundation (2002). Address correspondence to L.S.F., Department of Radiology, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France (e-mail: laure.fournier{at}gmail.com).


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively evaluate the ability of macromolecular contrast medium (MMCM)–enhanced dynamic magnetic resonance (MR) imaging to depict vascular changes in response to cyclooxygenase-2 (COX-2) inhibition of angiogenesis in a human breast cancer model.

Materials and Methods: The institutional committee for animal research approved this study. A human breast cancer cell line, MDA-MB-231, was implanted in 30 female homozygotous athymic rats that were alternately assigned to either a drug treatment group that received celecoxib on a daily basis for 7 days or a control group that received saline. Each animal underwent MR imaging after intravenous administration of a high-molecular-weight contrast agent at baseline and again 24 hours and 7 days after administration. Eleven rats in each group successfully underwent all three studies and had data sets of sufficient technical quality. A bidirectional two-compartment tissue model was used to estimate transendothelial permeability (KPS) and fractional plasma volume (fPV) for each tumor. Microvessel density was also measured to enable histologic assessment of angiogenesis. Repeated-measures analysis of variance and unpaired two-tailed t tests were used to evaluate differences in mean values between MR examinations performed in the same rats and between baseline values in treated and control rats, respectively.

Results: MR imaging–assayed microvascular KPS decreased significantly after 7 days of treatment with celecoxib (P < .05), but it was not significantly changed after 7 days in the control group. Likewise, microvascular density, a histologic surrogate of angiogenesis, was significantly (P < .05) lower in the treatment group than in the control group. The fPV did not significantly change in either group.

Conclusion: Dynamic MR imaging revealed microvascular permeability to a high-molecular-weight contrast agent was significantly reduced by treatment with celecoxib.

© RSNA, 2007

One approach to improve the survival rate of patients with cancer is to enhance our ability to characterize the specific biologic features of individual tumors and to monitor the response of each cancer to treatment. By monitoring individual lesion response, even before there has been a detectable change in tumor size, one is able to more quickly and rationally tailor therapy on an individual basis.

Inhibition of tumor angiogenesis has received the attention of researchers and the lay press: In 2004, the U.S. Food and Drug Administration approved the use of the first antiangiogenic anticancer drug, bevacizumab (Avastin; Genentech, South San Francisco, Calif), which inhibits the vascular endothelial growth factor (VEGF) and was originally approved for treatment of colorectal cancer (1). However, direct inhibition of VEGF is just one of several strategies to therapeutically attack the angiogenesis process. Additional drug therapy strategies with potential antiangiogenesis activity include VEGF receptor inhibitors, VEGF traps, endothelial nitric oxide synthetase inhibitors, and cyclooxygenase-2 (COX-2) inhibitors. Each strategy influences angiogenesis in a different manner.

One proposed magnetic resonance (MR) imaging method for noninvasively characterizing the vascularity of cancers and thereby assaying angiogenesis involves the use of a high-molecular-weight tracer or macromolecular contrast medium (MMCM) in conjunction with a two-compartment model (2–11). MMCM-enhanced MR imaging has been used experimentally to quantitatively assay tumor blood volume and vascular leakiness. This MMCM-enhanced MR method has been applied successfully to grade tumor aggressiveness (3), to monitor the antiangiogenic activity of anti-VEGF antibodies (Avastin; Genentech) in both a breast cancer model (9) and an ovarian cancer model (12), and to monitor activities of VEGF receptor antagonists (13) and matrix metalloproteinase inhibitors (14). However, to our knowledge, the full range, sensitivity, and robustness of this MR approach for monitoring drug treatment of antiangiogenesis have yet to be defined. Among the newly proposed pathways to inhibit angiogenesis is the use of COX-2 inhibitors, known generally for their antiinflammatory properties (15–17). To our knowledge, the effects of COX-2 inhibitors on tumor microvascularity, however, have not been evaluated with noninvasive imaging. We hypothesized that COX-2 inhibition of tumor angiogenesis can be detected and monitored for effectiveness with MMCM-enhanced MR imaging. Thus, the purpose of our study was to prospectively evaluate the ability of MMCM-enhanced dynamic MR imaging to depict vascular changes in response to COX-2 inhibition of angiogenesis in a human breast cancer model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Schering (Berlin, Germany) provided the contrast agent SH L 643A (Gadomer-17). The authors maintained control of the data and information submitted for publication.

Animal Model
This study was approved by the institutional committee for animal research and was performed in accordance with the guidelines of the National Institutes of Health for the care and use of laboratory animals.

The human MDA-MB-231 adenocarcinoma cell line (ATCC, Rockville, Md), which is known to express high levels of COX-2 enzyme (18), was cultured in a medium supplemented with 10% fetal calf serum and maintained in a humidified 5% CO2 atmosphere at 37°C. Cells were harvested by means of treatment in a solution of ethylenediaminetetraacetic acid and trypsin, washed in buffered saline, and centrifuged at 200 g for 5 minutes. Breast carcinoma induction was obtained by means of subcutaneous injection of 5 x 106 cancer cells suspended in 0.5 mL of phosphate-buffered saline and Matrigel (BD Bioscience, San Jose, Calif) in the flank of 30 female 4-week-old athymic homozygous nude rats (Harlan, Indianapolis, Ind). Animals were monitored for tumor growth every 2nd day. The MR imaging protocol was initiated when tumors reached a diameter of 1.0–1.5 cm. Rats were anesthetized before imaging by means of intraperitoneal injection of 50 mg of sodium pentobarbital per kilogram of body weight. A 25-gauge butterfly catheter was inserted into the tail vein for injection of the contrast agent during the MR examination. Rats were placed in the supine position on a heated water pad to avoid heat loss.

MR Imaging
MR imaging was performed with a 2-T Omega CSI-II system (Bruker Instruments, Fremont, Calif) equipped with Acustar S-150 (Bruker Instruments) self-shielded gradient coils (0.002 T/cm, 15-cm inner diameter). Animals were placed in birdcage radiofrequency coils with an inner diameter of 5.5 cm. Precontrast longitudinal relaxation times (R1 = 1/T1) were calculated for each tumor before contrast medium injection by using a spoiled gradient-recalled acquisition in the steady state sequence that involved nine repetition times that varied from 30 to 1000 msec (90° flip angle) and a monoexponential curve fit. Tumor-bearing rats were examined with multisection T1-weighted three-dimensional spoiled gradient-recalled acquisition in the steady state sequences before and during contrast agent administration. T1-weighted three-dimensional images were obtained with these sequences by using the following parameters: repetition time msec/echo time msec, 50.0/1.4; flip angle, 90°; number of signals acquired, one; matrix, 128 x 128 x 32; section thickness, 3 mm; and field of view, 50 x 50 x 96 mm (pixel size, 0.4 x 0.4 x 3.0 mm). Three precontrast images were acquired to establish a baseline. For the first 6 minutes after contrast medium administration, a keyhole technique (19) with a 128 x 32 x 16 data matrix was applied. This technique yielded 40 images at a rate of one image per 9 seconds. This technique was followed by acquisition of 20 complete sets of non-keyhole spoiled gradient-recalled acquisition images, each with an acquisition time of 2.2 minutes. The total image acquisition time was 50 minutes.

A high-molecular-weight contrast agent, SH L 643A (molecular weight, 17 kDa), was administered with a gadolinium concentration of 0.1 mmol/kg. This contrast agent is a dendrimer that contains 24 gadolinium polymers on its surface. In plasma, its R1 and R2, respectively, are 18.7 L · mmol–1 · sec–1 and 29.0 L · mmol–1 · sec–1 at 20 MHz and 40°C. Because of its globular configuration, it behaves much like a 35-kDa molecule in solution. Its plasma half-life in rats is estimated to be 60 minutes, and it exhibits complete renal elimination over the course of several days.

Kinetic Analysis of MR Imaging Data
On the basis of our knowledge of precontrast R1 values and precontrast signal intensity, postcontrast R1 values were derived from dynamic postcontrast signal intensity data (20). Subsequently, the change in R1 values ({Delta}R1) was calculated as a function of time and used as a direct proportional indicator of gadolinium tracer concentration in kinetic modeling (21). An author (L.S.F.) used an image analysis program (MR Vision, Menlo Park, Calif) to draw regions of interest on the typically strongly enhancing tumor rim and on the blood in the inferior vena cava used as the input function to determine signal intensity values for each time point.

The dynamic change in R1 (as a function of time) data from the inferior vena cava and tumor rim were analyzed by using a two-compartment equilibrating tissue model that comprised the plasma (blood was corrected for hematocrit) and interstitial spaces of the tumor. The response in the inferior vena cava, the input (forcing) function to the plasma space of the tissue model (after adjusting for hematocrit and a proportionality constant equal to the fractional plasma volume [fPV]), was fitted by using a biexponential function. The model enabled us to estimate the fPV of the tumor tissue (measured in milliliters per 100 mL of tissue) and to measure the transendothelial permeability (KPS, measured in milliliters per minute per 100 mL of tissue) of SH L 643A across the endothelium into the interstitial space of the tumor. The change in R1 (as a function of time) data from the inferior vena cava and tumor rim were fitted concurrently with a commercially available computer program (SAAM II; SAAM Institute, Seattle, Wash). This software uses standard variance-weighted nonlinear regression, the fractional standard deviation of the data that are assumed to be known within a proportionality constant (22). The precision of the estimates of the model parameters was determined from the covariance matrix at the least-squares fit.

The fPV is a parameter of the model. The KPS values are calculated by multiplying fPV by the fractional rate of contrast media leakage from plasma to the interstitial space of tumor tissue and then multiplying this product by 100.

COX-2 Inhibitor Administration
The rats were divided into two groups: a treatment group that received the active molecule (n = 17) and a control group that received saline (n = 13).

A 20 mg/kg dose of celecoxib (Celebrex; Searle, Chicago, Ill) was administered orally by means of gavage each day for 7 days in the treated rats. The celecoxib dose was based on the highest tolerated dose per weight that had been used in mice (23). Celecoxib was purchased in tablet form, and a solution was prepared for oral administration. The tablet was suspended in a vehicle that contained 0.5% methyl cellulose (Sigma-Aldrich, St Louis, Mo) and 0.025% Tween-20 (Sigma-Aldrich) in a solution of double-distilled water. Gavage was used to administer an equivalent volume of saline to rats in the control group.

Baseline MR images were obtained before celecoxib or saline administration (day 0). Celecoxib or saline was administered on day 1. Posttreatment MR examinations were performed on day 2 (24 hours after the first dose was administered) and on day 7 (approximately 1 hour after the seventh and final dose had been administered) (Fig 1).


Figure 1
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  		Figure 1: Time line and representative MR images show the treatment and imaging protocol. When the tumors grew to be 1.0–1.5 cm in diameter, they were examined with MR imaging (day 0). Celecoxib or saline administration began the next day (day 1). Tumors were examined again 24 hours after the first dose was administered (day 2). Celecoxib treatment and saline administration continued for 7 days. The final MR examination was performed approximately 1 hour after the seventh dose of celecoxib or saline was administered (day 7).

 
Histologic Analysis
At the end of the protocol, animals were sacrificed with intravenous administration of sodium pentobarbital and bilateral thoracotomies performed immediately after the second posttreatment MR examination. Tumors were resected, fixed in 10% buffered formalin, processed in paraffin, and sectioned in the same plane as the MR images. Conventional hematoxylin-eosin staining was performed, and histologic evaluation of tumors was performed with CD31 staining for microvascular densities after 7 days of administration of celecoxib or saline. Positively stained microvascular profiles were counted by using Image-Pro Plus (Media Cybernetics, Silver Spring, Md) and a BX60 microscope (Olympus, Center Valley, Pa) (magnification, x20) equipped with a DKC-ST5 digital camera (Sony Electronics, Park Ridge, NJ). Counts (expressed in number of vessels per field of view) were summed from 20 fields where the microvessel densities were highest, according to the method described by Weidner (24). Analysis was performed by two pathologists (T.M., E.F.) with 20 and 12 years of experience, respectively, who had no knowledge of MR imaging findings.

Statistical Analysis
Pre- and posttreatment mean KPS and fPV values in treated and control rats were compared in the same tumors by using repeated-measures analysis of variance (Statview 5.0.1; SAS Institute, Cary, NC). If a significant difference was detected, the Tukey-Kramer multiple comparison test was performed to determine where the difference occurred. Baseline mean values for KPS and fPV in control rats and treated rats were compared by using unpaired two-tailed Student t tests. The same strategy was used to compare mean microvessel density in control rats with that in treated rats. A P value of less than .05 was considered to indicate a statistically significant difference. All results were expressed as means ± standard deviations.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Tumors grew to be 1.0–1.5 cm in diameter in 8–21 days. When tumors reached this size, baseline MR imaging was performed and treatment was initiated. The mean tumor volume at baseline, as measured with MR imaging, was 1306 mm3 ± 1270.

Examinations Performed
Of the 17 rats initially assigned to the treatment group, only 12 successfully completed all three imaging examinations. Data obtained in one of these 12 rats were excluded from further analysis because of excessive image noise; thus, there were 11 complete data sets in the treatment group. High-quality complete data sets were obtained with all three MR examinations and used for analysis in 11 of the 13 rats in the control group. Our criteria for suitability of data for kinetic analysis were that the rat had successfully completed all three imaging examinations and that data from all three studies were satisfactory (ie, they had noise levels low enough to result in relatively well-determined model parameters [coefficient of variation ≤ 10%]). For the 22 tumors (11 in the treatment group and 11 in the control group) that were included in the final analysis, regions of interest were successfully placed on the inferior vena cava and tumor rim for all 66 studies. Mean region of interest size was 23 pixels for the tumor rim and 7 pixels for the inferior vena cava.

In each of the 66 MR data sets, the two-compartment model enabled satisfactory data fitting. The uncertainty estimates (coefficient of variation, expressed as a percentage) for fPV and KPS were within preset limits (≤10%); the mean values varied from 3% to 6% depending on the parameter and group studied.

Treatment and Control Groups
Before treatment, the mean KPS values in the treatment and control groups were not significantly different (0.89 mL · min–1 · 100 mL–1 of tissue ± 0.33 and 0.88 mL · min–1 · 100 mL–1 of tissue ± 0.29, respectively; P = .91) (Fig 2, Table). On day 7, mean KPS values were significantly (P = .021) lower than baseline KPS values in the treatment group (0.65 mL · min–1 · 100 mL–1 of tissue ± 0.16 vs 0.89 mL · min–1 · 100 mL–1 of tissue ± 0.33) but virtually unchanged (P = .51) in the control group (0.89 mL · min–1 · 100 mL–1 of tissue ± 0.39 vs 0.88 mL · min–1 · 100 mL–1 of tissue ± 0.29). There was a nonsignificant (P = .09) tendency for mean KPS values to decrease 24 hours after celecoxib treatment was initiated, as compared with baseline KPS values (from 0.89 mL · min–1 · 100 mL–1 of tissue ± 0.33 to 0.69 mL · min–1 · 100 mL–1 of tissue ± 0.30).


Figure 2
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  		Figure 2: Histogram shows mean KPS values and standard deviations (error bars) at baseline and at 1 day and 7 days after administration of celecoxib (Treated) or saline (Controls). There was a significant difference (*) between baseline KPS values (x-axis, in milliliters per minute per 100 mL of tissue) and KPS values at day 7 in the rats treated with celecoxib.

 

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  		KPS and fPV Values in Rats

 
There was no significant difference between (a) baseline fPV values in the treatment group and those in the control group (4.5 mL/100 mL of tissue ± 1.3 vs 5.5 mL/100 mL of tissue ± 1.7), (b) fPV values in the treatment group at baseline, 24 hours, and day 7 (4.5 mL/100 mL of tissue ± 1.3, 4.1 mL/100 mL of tissue ± 1.4, and 4.0 mL/100 mL of tissue ± 1.2, respectively); or (c) fPV values in the control group at baseline, 24 hours, and day 7 (5.5 mL/100 mL of tissue ± 1.7, 6.0 mL/100 mL of tissue ± 1.5, and 5.6 mL/100 mL of tissue ± 1.5, respectively).

Histologic Analysis
At the end of the MR protocol, histologic analysis revealed that tumors in the control group had a mean microvessel density of 358 vessels ± 127, whereas tumors in the treated group had a significantly (P = .03) lower mean microvessel density of 257 vessels ± 84 (Fig 3). This finding enabled us to confirm that angiogenesis had been inhibited.


Figure 3A
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  		Figure 3a: Representative light microscopic sections from two tumors immunohistochemically stained for CD31 and specific for endothelial cells (arrows), which stain dark brown. (Hematoxylin-eosin stain; original magnification, x20.) (a) Section shows tumors in a control rat have high microvessel density. (b) Section shows a tumor has much lower vessel density after 7 days of antiangiogenic treatment with celecoxib.

 

Figure 3B
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  		Figure 3b: Representative light microscopic sections from two tumors immunohistochemically stained for CD31 and specific for endothelial cells (arrows), which stain dark brown. (Hematoxylin-eosin stain; original magnification, x20.) (a) Section shows tumors in a control rat have high microvessel density. (b) Section shows a tumor has much lower vessel density after 7 days of antiangiogenic treatment with celecoxib.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
The results of this study show that dynamic MR imaging performed with a high-molecular-weight contrast agent in conjunction with a simple compartmental model can be used to detect and quantitatively measure significant declines in apparent tumor permeability within 7 days after initiation of therapy with the COX-2 inhibitor celecoxib. With use of an MDA-MB-231 human breast cancer xenograft model, the celecoxib-induced inhibition of angiogenesis was confirmed with histologic analysis on the basis of a corresponding significant reduction in microvessel density, which is a widely used pathologic surrogate of angiogenesis (24).

The fPV estimates obtained with MR imaging indicated that COX-2 tumor therapy of 7 days duration did not significantly reduce the fPV values; this result was taken to reflect the richness of vascularity within the tumor. The tumor rim was assessed rather than the whole tumor because the center of the tumor tended to develop necrosis, which made evaluation of the microvascular status of the tumor problematic.

The MDA-MB-231 tumor model was chosen for this study because it is a form of human breast cancer that is known to overexpress the COX-2 enzyme (18). COX-2 therapy was chosen because the findings of epidemiologic studies have shown that individuals who regularly take nonsteroidal antiinflammatory drugs, which nonspecifically block the COX-2 enzyme to relieve inflammatory conditions, have lower incidences of colorectal polyps and a lower rate of death from colorectal cancer or breast cancer (25). Interestingly, the COX-2 enzyme is overexpressed not only by tumor cells but also by vascular endothelial cells (26) of a number of cancers, including colon, prostate, lung, and breast cancers (27). The COX-2 enzyme also has been linked to vascular permeability. In a VEGF-dependent permeability model in guinea pigs, COX-2 inhibition was shown to inhibit vascular permeability to Evan blue, which is a protein-bound dye (28). This finding is consistent with our results. Of topical interest, recent reports have suggested that COX-2 inhibitors are associated with an increased risk of cardiovascular events. The potential risks of COX-2 inhibition will need to be considered before COX-2 inhibitors are used for anticancer treatment (29–31).

Our study had certain limitations. The COX-2 inhibition treatment lasted only 7 days. This short treatment period was selected to demonstrate the early effects of antiangiogenic treatment and the capacity of MR imaging to depict the effects of treatment, even before evidence of retarded tumor growth. Also, the study was terminated after 1 week of observation to prevent potential animal suffering due to continued unbridled tumor growth in the control group. Celecoxib had been previously used by others to induce tumor growth inhibition in rodent breast cancer models: Alshafie et al (32) found that rat mammary tumor growth was slowed significantly in 90% of the animals when a daily oral dose of celecoxib was administered. These growth inhibition effects, however, were seen only after prolonged therapy (approximately 1 month), and these studies did not include MR assays. In our study, we chose to validate the MR imaging–assessed inhibitory effect on angiogenesis by examining the microvascular density, which is a histologic surrogate of angiogenesis. This allowed us to sacrifice the animals after a 7-day course of treatment with celecoxib and before any effect on growth was expected or ultimately manifested.

The contrast material–enhanced MR imaging technique used to monitor angiogenesis inhibition in this study is not yet ready for translation to clinical practice. A major obstacle is that the contrast agent (SH L 643A) used in our study is not yet approved for clinical use, and other candidate MMCMs previously tested in quantitative assays of tumor permeability are not yet available for use in routine clinical practice. The use of MMCMs in the assessment of tumor microvascular permeability is interesting, since tumor vessels are highly disorganized and leaky to large molecules that do not pass a normal endothelial barrier (33–38). SH L 643A and other MMCMs, such as ultrasmall superparamagnetic iron oxide particles, are now being evaluated in clinical trials and potentially could be applied to angiogenesis assessments in the near future (4).

Practical applications: Experimental data acquired from a human breast cancer model in athymic rats show that an MMCM-enhanced dynamic MR imaging technique can generate useful depictions of tumor microvessels within 24 hours after treatment initiation and before any detectable change in tumor size. The same technique of kinetic analysis of MMCM-enhanced MR images to generate estimates of KPS and fPV had been shown previously to enable detection of (a) early tumor responses to anti-VEGF antibodies (Avastin; Genentech) both in human xenograft breast cancers (9) and in human xenograft ovarian cancers (12), (b) breast cancer responses to inhibitors of VEGF receptors located on the endothelial cell surface (2,13), and (c) the antitumor effect from a matrix metalloproteinase inhibitor (14). These results are noteworthy in several respects. If the findings are translatable and applied clinically, oncologists should be able to determine whether a patient will respond to a specific antiangiogenic drug as early as 1 day after treatment instead of relying on changes in tumor size, which are often delayed weeks or months and are nonspecific. The results are also important in demonstrating the potential role of MMCM-enhanced MR imaging in monitoring tumor response to chemotherapy.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: COX-2 = cyclooxygenase-2 • fPV = fractional plasma volume • KPS = transendothelial permeability • MMCM = macromolecular contrast medium • VEGF = vascular endothelial growth factor

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, L.S.F., R.C.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, L.S.F., V.N., V.L., R.C.B.; experimental studies, L.S.F., V.N., V.L., Y.F., T.M., E.F.; statistical analysis, L.S.F., D.M.S., R.C.B.; and manuscript editing, all authors


   References
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 RESULTS
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 ADVANCES IN KNOWLEDGE
 References
 

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