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Published as doi: 10.1096/fj.07-103713.
 (The FASEB Journal. 2008;22:2445-2451.)
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Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

Dawen Zhao, Edmond Richer, Peter P. Antich and Ralph P. Mason1

Department of Radiology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

1Correspondence: Department of Radiology, University of Texas Southwestern Medical Center, 5523 Harry Hines, Dallas, TX 75390-9058, USA. E-mail: ralph.mason{at}utsouthwestern.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Bioluminescence imaging (BLI) has found significant use in evaluating long-term cancer therapy in small animals. We have now tested the feasibility of using BLI to assess acute effects of the vascular disrupting agent combretastatin A4 phosphate (CA4P) on luciferase-expressing MDA-MB-231 human breast tumor cells growing as xenografts in mice. Following administration of luciferin substrate, there is a rapid increase in light emission reaching a maximum after about 6 min, which gradually decreases over the following 20 min. The kinetics of light emission are highly reproducible; however, following i.p. administration of CA4P (120 mg/kg), the detected light emission was decreased between 50 and 90%, and time to maximum was significantly delayed. Twenty-four hours later, there was some recovery of light emission following further administration of luciferin substrate. Comparison with dynamic contrast-enhanced MRI based on the paramagnetic contrast agent Omniscan showed comparable changes in the tumors consistent with the previous literature. Histology also confirmed shutdown of tumor vascular perfusion. We believe this finding provides an important novel application for BLI that could have widespread application in screening novel therapeutics expected to cause acute vascular changes in tumors.—Zhao, D., Richer, E., Antich, P. P., Mason, R. P. Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI.


Key Words: breast tumor • vascular targeting agent • vascular disrupting agent • pharmacodynamics


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BIOLUMINESCENCE IMAGING (BLI) has found a major role in small animal research (1 2 3) . For tumor cells transfected to constitutively express luciferase, there are numerous reports examining tumor growth and metastatic spread (4 , 5) . BLI has also found widespread use in examining changes in tumor growth over a period of many weeks with diverse therapies (6 7 8 9 10) . BLI requires administration of luciferin substrate, which may be achieved by multiple routes, including intravenous (i.v.), intraperitoneal (i.p.), or subcutaneous (s.c.) (11 , 12) . Luciferin is then carried throughout the vasculature and has been shown to readily permeate every region of the body (9 , 13 , 14) . Given the importance of vascular transport, it occurred to us that the measurement of the light-emitting dynamics would be related to vascular delivery of the substrate. Thus, any agent causing major acute affects on tumor vasculature could influence the light emission kinetics. In particular, it appeared that vascular targeting agents (VTAs; also referred to as vascular disrupting agents), such as combretastatin, could be assessed based on the dynamics of light emission detected by BLI.

Tumor growth, survival, and metastasis depend critically on the development of new blood vessels (15) . Therefore, extensive research has focused on developing strategies to attack tumor vasculature (16 17 18 19) . Tubulin-binding agents (e.g., combretastatin A-4-phosphate (CA4P) and ZD6126) represent one kind of VTA (17) . Promising preclinical studies have shown that such agents selectively cause tumor vascular shutdown and subsequently trigger a cascade of tumor cell death in experimental tumors (20) . Although massive necrosis can be induced, tumors usually regrow from a thin viable rim. To better understand the mode of action and, hence, facilitate optimized therapeutic combinations, in vivo imaging approaches have been applied to monitor physiological changes resulting from VTA administration (21 22 23) . Dynamic contrast-enhanced (DCE) MRI based on the transport properties of the small paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) is the most commonly used imaging approach to study tumor vascular perfusion and permeability. DCE MRI was included as part of the Phase I clinical trials of CA4P (24 , 25) . Results of preclinical and clinical DCE MRI studies have shown a reversible change in vascular perfusion in the tumor periphery following a single dose of VTA (26 27 28 29) .

The VTA CA4P causes tumor vascular shutdown, inducing massive cell death. We recently showed acute hypoxiation within 90 min following CA4P administration to rats bearing syngeneic breast 13762NF tumors using MRI (30) . Rapid vascular shutdown in tumors after administration of CA4P to animals and patients has also been observed by many other imaging modalities, including positron emission tomography based on the distribution of 15O water (31) , DCE MRI (24 , 32 , 33) , DCE computed tomography (CT) (34) , 19F MRI of tumor oxygenation (30) , laser Doppler flowmetry (35) , radiolabeled iodoantipyrine uptake (27) , near infrared spectroscopy (36) , interstitial fluid pressure (35) , and intravital microscopy (37) . By comparison, BLI is particularly inexpensive and easy to apply in animal models, and we believe it could be an effective screening tool for evaluation and comparison of vascular targeting agents as well as long-term tumor growth. BLI is exceedingly sensitive with the capability of detecting subpalpable tumor volumes.

We have now explored the ability of planar BLI, a widely available modality, to investigate the acute effects of CA4P on human breast MDA-MB-231 xenograft tumors and provide correlates with the more traditional MRI approach and histology.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor model
Human mammary MDA-MB-231 cells were infected with a lentivirus containing a firefly luciferase reporter, and highly expressing stable clones were isolated. Tumors were induced by injecting 106 cells subcutaneously in the flank of 13 athymic nude mice (BALB/c nu/nu; Harlan, Indianapolis, IN, USA). Tumors were allowed to grow to ~6 mm diameter (~100 mm3) and then selected for BLI or MRI.

In vivo BLI
Tumor-bearing mice were anesthetized (isoflurane/O2 in an induction chamber; isoflurane from Baxter International Inc., Deerfield, IL, USA) and a solution of D-luciferin (450 mg/kg in PBS in a total volume of 250 µl; Biosynthesis, Naperville, IL, USA) was administered s.c. in the neck region. Anesthesia was maintained with isoflurane (1%) in oxygen (1 dm3/min) and a series of light images (60 s each) was acquired using a single reference camera of our multicamera Light Emission Tomography System over a period of 20–30 min and the light intensity-time curves evaluated.

The imaging system uses CCD (charge-coupled device) cameras selected for their high and nearly constant sensitivity over the full range of wavelengths commonly used in optical imaging, from blue to near infrared. The CCD is a noncolor, back-illuminated, full-frame image sensor with 512 x 512 pixels [(SITe) SI-032AB CCD; Scientific Imaging Technologies Inc., Tigard, OR, USA]. The quantum efficiency of the CCD is greater than 85% from 400–750 nm, and remains above 50% up to 900 nm. The CCD has a pixel size of 24 x 24 µm, providing a large well capacity of 350,000 e–, with a sensitivity of 2.6 µV/e–, low dark current (20 pA/cm2 at 20°C), and low readout noise (5 e– RMS), providing a dynamic range of 75,000. The CCD is cooled to –40°C, reducing the dark current signal to less than 0.1 e–/pixel/s. The large dynamic range of the detector is coupled with a 16 bit analog to digital converter, allowing quantitative detection of both high and very low signals simultaneously. The CCD is incorporated in a self-contained, cooled camera equipped with electronic circuitry and fast optics (25 mm focal length, f/0.95). Each camera is calibrated using a low-intensity, diffuse, flat-field source that gives a known radiance (adjusted typically at 3.0x10–7 W/cm2/sr). The light source is periodically checked for uniformity using a NIST-traceable research radiometer (model IL 1700; International Light, Inc. Newburyport, MA, USA). By imaging this source, the digital units provided by the camera digitizer can be converted directly into absolute physical units (W/cm2/sr or photons/s/cm2/sr).

Saline control or combretastatin A4P (CA4P; 120 mg/kg; OXiGENE, Inc. Waltham, MA, USA) in saline (120 µl) was injected i.p. immediately after baseline BLI and the mouse allowed to wake up. Two hours later, the BLI time course was repeated based on new injections of luciferin. In some cases, mice were examined again 24 h after CA4P administration.

In vivo MRI
A second cohort of nude mice (n=3) with size-matched tumors was studied by MRI using a 4.7 T horizontal bore magnet with a Varian INOVA Unity system (Palo Alto, CA, USA). Each mouse was maintained under general anesthesia (air and 1% isoflurane). A 27 G butterfly (Abbott Laboratories, Abbott Park, IL, USA) was placed in a tail vein for contrast agent administration. Pertinent image slice positions were based on fast scout images. T1-weighted (TR=200 ms; TE=15 ms; slice thickness=1.5 mm; FOV=50x50; in plane resolution 390 µm) and corresponding T2-weighted (TR=1500 ms; TE=80 ms) spin-echo multislice axial images were acquired. For DCE MRI, a series of 3 contiguous T1-weighted images (TR=70 ms; TE=12 ms; total acquisition time 10 s with same voxel dimensions as above) was acquired before and after i.v. bolus injection of the contrast agent Gd-DTPA-BMA (0.1 mmol/kg body weight; OmniscanTM, Amersham Health Inc., Princeton, NJ, USA) through a tail vein catheter. DCE MRI was performed before and 2 h after CA4P infusion (120 mg/kg, i.p.).

Data were processed on a voxel-by-voxel basis using software written by us using IDL 5.3/5.4 (Research Systems, Boulder, CO, USA). For each slice, the tumor was separated into regions of center and periphery, respectively. The tumor periphery was taken to be a 1–2 mm thick rim aligned around the whole tumor. Signal intensity vs. time curves were plotted and relative signal intensity changes ({Delta}SI) of each tumor voxel were analyzed using the equation {Delta}SI = (SIE –SIb)/SIb, where SIE is enhanced signal intensity in the voxel, and SIb is the average of the baseline images. The area under the normalized signal intensity-time curve (IAUC) was integrated for the first 60 s after Gd-DTPA-BMA injection.

Immunohistochemistry
Two hours after saline or CA4P injection, the blue fluorescent dye Hoechst 33342 (10 mg/kg, Molecular Probes, Eugene, OR, USA) was injected into the tail vein of anesthetized mice, and the tumors were excised 1 min later. Tumor specimens were immediately immersed in liquid nitrogen and then stored at –80°C. A series of 6 µm frozen sections from several regions of each tumor was immunostained for luciferase (Serotec Inc., Raleigh, NC, USA). Slices were imaged for Hoechst 33342 under ultraviolet (UV) wavelengths (330–380 nm). Perfused vessels were determined by counting the total number of structures stained by Hoechst 33342 in 4 fields per section selected to show high perfusion and calculating the mean number of vessels per square millimeter. On the following day, the same slices, as well as the adjacent ones, were immunostained for the endothelial marker, CD31. A primary rat anti-mouse CD31 monoclonal antibody (1:20 dilution; Serotec) was added and incubated overnight at 4°C in a humid box. Slides were incubated with Cy3-conjugated goat anti-rat secondary antibody (1:100 dilution; Jackson Immunoresearch Laboratories, West Grove, PA, USA) for 1 h at 37°C. After mounting with Vectorshield® medium (Vector Laboratories, Burlingame, CA, USA), the slides were observed under red fluorescence (530–550 nm excitation) to detect anti-CD31 and then the corresponding Hoechst 33342 again under UV light. Image analysis was performed using Metaview software (Universal Imaging Corp., West Chester, PA, USA). For luciferase staining, monoclonal mouse antiluciferase mAb (1:150; Serotec) and fluorescein isothiocyanate-conjugated goat anti-mouse secondary antibody (Jackson) were used.

Statistical analysis
Statistical significance was assessed using an ANOVA on the basis of Fisher’s protected least significant difference (PLSD; Statview; SAS Institute Inc., Cary, NC, USA) or Student’s t tests.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histology of MDA-MB-231-luc cells showed extensive expression of luciferase detected by antiluc mAb in all tumor cells (Fig. 1 ). BLI showed intense light emission from tumors following s.c. administration of luciferin reaching a maximum intensity ~6 min postadministration followed by a gradual decline over the next 20 min. Repeat measurements following administration of a second dose of luciferin 2 h after injecting saline i.p. showed highly reproducible results (Fig. 1 , Table 1 ) in terms of light distribution, maximum light intensity, and time to maximum light emission. Five tumors were examined again after 24 h, and light emission remained highly consistent, with mean maximum intensity = 97 ± 6% (range 49–130%). By contrast, repeat BLI 2 h after treatment with CA4P showed a significantly lower light emission (peak intensity 2–10x lower) and delayed peak emission (Fig. 2 ; Table 1 ). Three mice were examined again 24 h post-CA4P, and signal was again significantly lower than baseline (mean 41±5, range 21–66%), though with some recovery compared with 2 h. Histology showed a well-developed, well-perfused vasculature in these tumors, but perfusion was essentially eliminated 2 h after administration of CA4P i.p. (Fig. 3 ).


Figure 1
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  		Figure 1. Control BLI dynamic measurement. A) Staining for luciferase in an MDA-MB-231-luc tumor tissue section showed extensive fluorescent mAb signal predominantly located in cytoplasm of many tumor cells. B) Bioluminescent image from a representative MDA-MB-231-luc tumor (140 mm3) acquired in 1 min, 4 min after luciferin injection (450 mg/kg s.c.). C) Bioluminescent image from the same tumor following repeat s.c. luciferin injection 2 h after saline injection (0.15 ml i.p.). D) The BLI intensity was integrated over the whole tumor, and the time course was essentially identical for the 2 investigations conducted 2 h apart with respect to saline administration, as a control. Maximum signal intensity was observed at 6 min after s.c. luciferin administration.


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  		Table 1. MDA-MB-231-luc mammary carcinoma response to CA4P observed by BLI


Figure 2
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  		Figure 2. Tumor response to CA4P monitored by planar BLI. A second MDA-MB-231-luc tumor (130 mm3) was monitored sequentially following saline or CA4P (120 mg/kg) i.p. infusion. Each image was acquired in 1 min, 4 min after s.c. luciferin injection. In contrast to saline, CA4P treatment caused a significant decrease in BLI signal intensity 2 h after treatment, which remained lower 24 h later. A) Baseline control, B) 2 h after CA4P, C) BLI intensity curves showing intense signal pretreatment (solid squares) with 99% less signal 2 h after CA4P (open circles).


Figure 3
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  		Figure 3. Immunohistochemical study of tumor vascular response to CA4P. Perfusion marker Hoechst 33342 staining pre- and 2 h post-CA4P (120 mg/kg). Vascular endothelium of the same field was immunostained by anti-CD31 (red). A good match between Hoechst and anti-CD31 stained vascular endothelium was found in the pretreated tumor (overlay). Two hours after treatment, significant reduction in perfused vessels was detected. Scale bar = 100 µm.

Signal enhancement observed by DCE MRI was significantly less in all 3 tumors with a mean decrease of ~70% in perfusion/permeability 2 h after CA4P (P<0.001, Table 2 ,Fig. 4 ). Little change was observed in perfusion of the femoral artery (data not shown). Muscle in 1 mouse indicated a significant reduction in IAUC, but others showed no significant change (Table 2) .


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  		Table 2. DCE MRI data


Figure 4
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  		Figure 4. DCE MRI monitoring of tumor response to CA4P. A–C) Conventional MR images of a nude mouse with an MDA-MB-231-luc mammary tumor (Tumor 2 in Table 2 ): T1-weighted (A), T2-weighted (B), and T1-weighted (C) contrast-enhanced (Gd-DTPA-BMA). D, E) Dynamic contrast-enhanced MRI was performed in the mouse before (D) and 2 h after (E) CA4P i.p. injection. Color scale map = normalized contrast enhancement 30 s after a bolus injection of Gd-DTPA-BMA is overlaid on the T1-weighted images. Significantly decreased signal enhancement, compared with pretreatment, was observed 2 h after i.p. injection of CA4P. F) Ratio of tumor:muscle signal enhancement following infusion of Gd-DTPA-BMA in the single image slice shown in D and E. Solid symbols = baseline; open symbols = 2 h after CA4P.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Following administration of the vascular targeting agent CA4P, BLI showed significantly decreased and delayed signal in the human mammary MDA-MB-231 carcinoma. We interpret this finding as due to induced vascular shutdown. Dynamic contrast-enhanced MRI confirmed decreased tumor perfusion, which was further confirmed by histology. Both BLI and MRI are noninvasive and depict the same physiological effects, but BLI is much cheaper and offers a high throughput method for evaluating novel drugs and drug combinations and scheduling.

BLI is a very sensitive technique revealing transfected cells at even subpalpable volumes. Signal is attenuated at depth, but the technique can be applied routinely in both s.c. models and for monitoring orthotopic tumor development (3 4 5 6 7 8 , 12) . Several groups have shown robust correlations between detected light and tumor volume assessed by calipers or MRI (5 , 12 , 38 , 39) . In our early work (12) , we found strong correlations (r>0.8) between peak light signal, initial area under the curve, or signal intensity at 10 min after luciferin infusion and tumor volume following i.p. administration of 150 mg/kg D-luciferin. However, individual measurements showed discrepancies, and consecutive observations could vary by as much as 60%. Overall estimates at 95% confidence intervals suggested error < 20%. We later established better reproducibility based on 450 mg/kg luciferin administered s.c. It is important to note that light-emission kinetics depend on tumor location. Thus, for HeLa-luc cells growing subcutaneously, we found maximum light-emission around 10 (median) and 12.7 (mean) min following i.p. administration, whereas in the current study, using s.c. mammary tumors and s.c. administration of luciferin, maximum light-emission occurred after ~7.5 min. In the current study, BLI repeated 2 h after saline injection showed light-emission kinetics highly consistent with baseline in terms of maximum light emission, time to maximum light emission, integrated light, and signal observed at 7 min (Table 1 ; Fig. 1 ). In 5 mice, BLI measurements were again repeated 24 h later, and light emission remained highly consistent (not significantly different from baseline or 2-h time points). Two hours after CA4P administration, light-emission kinetics were significantly altered with both delayed emission and reduced light intensity (Table 1) . Light-emission kinetics remained low 24 h later, when luciferin was readministered to a subgroup of mice.

Changes in vascular perfusion were confirmed by histology. These tumors show extensive vasculature as revealed by anti-CD31 staining, which is also extensively perfused (Fig. 3) . Two hours after CA4P administration, vasculature was detectable, but now there was no evidence of perfusion.

Dynamic contrast-enhanced MRI has been applied previously both in animal models and the clinic to many tumor types with respect to combretastatin administration (24 , 30 , 32) . The changes observed here (Fig. 4 ; Table 2 ) are consistent with previous observations (23 , 30) . Initial area under the curve reflects tumor blood flow, vascular permeability, and the involved fraction of interstitial space. For the initial control study, the signal enhancement was generally considerably greater in tumor than contralateral thigh muscle (Table 2 ; Fig. 4F ). Following combretastatin administration, the IAUC decreased significantly in each tumor with a mean of ~70% in tumors (Table 2) but was not significantly changed in 2 of 3 muscles. One mouse did show decreased perfusion of normal muscle after combretastatin, as also reported previously by Tozer et al. (23) in rats.

BLI is more traditionally used to assess tumor growth and metastatic spread rather than physiological effects. BLI enables detection of subpalpable volumes and deep-seated tumors in mice although this capability has not been exploited in the current study. BLI is noninvasive but does require administration of luciferin substrate. Thus, sampling tumor vasculature is only achieved at discrete time points following administration of the substrate. The requirement for a reporter substrate is common to other methods of interrogation also, such as DCE MRI or DCE CT, which require administration of paramagnetic or radio opaque contrast agents (24 , 30 , 32 , 34) . Radionuclide approaches can be applied similarly (31) , although they are more often used with autoradiography postmortem. Measurements based on Laser Doppler flowmetry (35) , pressure probes (35) , and NIR (36) may allow continuous sampling. Oximetry based on 19F MRI of hexafluorobenzene allowed essentially continuous mapping of pO2 changes with a 6.5 minute time resolution (30) .

One disadvantage of the BLI approach to assessing tumor vasculature is the need for luciferase-expressing cells. However, numerous cell lines are now widely available and effective stable transfection is readily achievable though clonal selection could lead to differences between luciferase-expressing and parental tumor lines.

While combretastatin (or Zybrestat) is now in Phase II/III clinical trials for anaplastic thyroid cancer, studies will continue to be required in preclinical settings to optimize combinations with other chemotherapeutic drugs or radiation in diverse tumor types. We believe BLI provides an optimal approach for examining acute pharmacodynamics together with the potential for long-term chronic assessment of tumor control or growth. This approach could be equally applicable to other VTAs, which cause significant acute changes in blood flow, such as ZD6126 or 5,6-dimethylxanthenone-4-acetic acid (19) .

There is increasing realization that drugs may behave differently with various tumor types and sites of implantation. The observations here are consistent with a previous report on the same tumor type, which showed extensive central necrosis 24 h after combretastatin administration while leaving a viable peripheral rim (20) . BLI will facilitate effective screening of many tumor types implanted subcutaneously or orthotopically and with respect to monotherapy or combinations. We believe this is the first report of the use of BLI to monitor acute effects of a drug on tumor vasculature and represents an additional application of this new technology.


   ACKNOWLEDGMENTS
 
This work was supported in part by the U.S. Department of Defense Breast Cancer Initiative Idea Awards to D.Z. (DAMD-170310363) and to P.P.A. (W81XWH-04–1-0551), the National Cancer Institute Cancer Imaging Program (pre-ICMIC CA86354 and U24 CA126608), and Simmons Cancer Center. NMR experiments were performed at the Advanced Imaging Research Center, a National Institutes of Health Biological Threat Reduction Program facility (P41-RR02584). Combretastatin A4 phosphate was a gift of OxiGene. We are grateful to Dr. Jerry Shay (Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA) for providing luciferase-expressing tumor cells, and to Drs. L. Liu and Y. Ren for generating the tumors. A. Harper and A. Contero performed the bioluminescent imaging.

Received for publication November 30, 2007. Accepted for publication January 10, 2008.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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