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Cancer Therapy: Preclinical |
Laboratories of 1 Biomedical Magnetic Resonance, 2 Medicinal Chemistry and Radiopharmacy, and 3 Pharmacology and Therapeutics and 4 Radiobiology and Radioprotection Unit, Université Catholique de Louvain, Brussels, Belgium
Requests for reprints: Bernard Gallez, CMFA/REMA Units, Université Catholique de Louvain, Avenue E. Mounier 73.40, B-1200 Brussels, Belgium. Phone: 32-2-7642792; Fax: 32-2-7642790; E-mail: Gallez{at}cmfa.ucl.ac.be.
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ABSTRACT |
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Experimental Design: Tumor oxygenation, perfusion, permeability, interstitial fluid pressure (IFP), and radiation sensitivity were studied in an FSAII tumor model. Mice were treated by daily i.p. injection of thalidomide at a dose of 200 mg/kg. Measurements of the partial pressure of oxygen (pO2) were carried out using electron paramagnetic resonance oximetry. Three complementary techniques were used to assess the blood flow inside the tumor: dynamic contrast-enhanced magnetic resonance imaging, Patent Blue staining, and laser Doppler imaging. IFP was measured by a "wick-in-needle" technique.
Results: Our results show that thalidomide induces tumor reoxygenation within 2 days. This reoxygenation is correlated with a reduction in IFP and an increase in perfusion. These changes can be attributed to extensive vascular remodeling that we observed using CD31 labeling.
Conclusions: In summary, the microenvironmental changes induced by thalidomide were sufficient to radiosensitize tumors. The fact that thalidomide radiosensitization was not observed in vitro, and that in vivo radiosensitization occurred in a narrow time window, lead us to believe that initial vascular normalization by thalidomide accounts for tumor radiosensitization.
Key Words: antiangiogenic • oxygen • flow • interstitial fluid pressure • radiotherapy
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antiangiogenic therapies have been proposed to gradually deprive a tumor of its blood supply (6). Although such approaches have had attractive results in animal models, they have been disappointing in clinical trials. This has prompted efforts to combine antiangiogenic treatments with other treatment modalities. The combination of antiangiogenic agents with radiotherapy has been suggested because it should target both the tumor cells and the endothelial cells. However, this strategy also seems counterintuitive: it is well established that conventional radiotherapy requires sufficient tumor oxygenation to avoid radioresistance, and antiangiogenic therapies should lead to a decrease in oxygen, thereby lowering radiosensitivity. A possible explanation for a potential synergistic effect is that the administration of antiangiogenic agent could first prune the immature and inefficient blood vessels and consequently result in an early "normalization" of the tumor vasculature (7). This hypothesis is further supported by studies that have blocked the signaling of vascular endothelial growth factor (a potent proangiogenic factor), which resulted in apoptosis of endothelial cells and a decrease in vessel diameter, density, and permeability (8–10). This consequently leads to a decrease in the IFP and an increase in tumor oxygen partial pressure (pO2; refs. 8, 11, 12).
The efficacy of combining antiangiogenic therapy with chemotherapy (13, 14) or radiotherapy (12, 15–17) has been recently reported. However, the net effect of antiangiogenic treatment on the evolution of the tumor microenvironment (including parameters such as pO2, perfusion, IFP, and their evolution with the time after treatment) has been neglected in many studies.
The purpose of the present study is to monitor the evolution of the tumor microenvironment early after an antiangiogenic treatment and to determine if there exists an optimal time window for cotreatment with radiotherapy. The antiangiogenic agent used in our study was thalidomide (one of the most studied antiangiogenic agents in clinical trials). Thalidomide was shown to inhibit basic fibroblast growth factor (18) as well as vascular endothelial growth factor (19, 20), two promoters of angiogenesis. A direct antitumor effect has been shown in rabbits (21) and humans (22).
In this work, we report a transient increase in tumor oxygenation 2 days after the beginning of the treatment, paralleling changes in tumor perfusion and interstitial pressure. At that time, tumors were radiosensitized. Such radiosensitization was absent when radiotherapy was delivered earlier or later, thereby emphasizing the need to monitor the tumor microenvironment when combining antiangiogenic treatments with radiotherapy.
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MATERIALS AND METHODS |
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Tumor Oxygenation
Electronic paramagnetic resonance (EPR) oximetry (using charcoal as oxygen-sensitive probe) was used to evaluate tumor oxygenation changes after thalidomide treatment using a protocol described previously (24–26). EPR spectra were recorded using an EPR spectrometer (Magnettech, Berlin, Germany) with a low-frequency microwave bridge operating at 1.2 GHz and an extended loop resonator. Mice were given injections in the center of the tumor 2 days before measurement using the charcoal suspension (100 mg/mL, 50 µL injected, 1- to 25-µm particle size). The localized EPR measurements correspond to an average of pO2 values in a volume of 
10 mm3 (25). To avoid any acute effect of the treatment, data acquisition was made before the first injection of thalidomide or DMSO and then on a daily basis for 1 week.
Flow Measurements
Patent Blue Staining. Patent Blue (Sigma-Aldrich) was used to obtain a rough estimate of the tumor perfusion (27) after 2 days of treatment with thalidomide or vehicle. This technique involves the injection of 200 µL of Patent Blue (1.25%) solution into the tail vein of the mice. After 1 minute, a uniform distribution of the staining through the body was obtained and mice were sacrificed. Tumors were carefully excised and cut into size-matched halves. Pictures of each tumor cross section were taken with a digital camera. To compare the stained versus unstained area, an in-house program running on Interactive Data Language (Research Systems Inc., Boulder, CO) was developed. For each tumor, a region of interest (stained area) was defined on the two pictures and the percentage of stained area of the whole cross section was determined. The mean of the percentages of the two pictures was then calculated and was used as an indicator of tumor perfusion.
Laser Doppler Imaging. Superficial tumor perfusion was assessed using a laser Doppler imager (Moor Instruments, Millwey, United Kingdom) after 2 days of treatment with thalidomide or vehicle. The skin was depilated the day before measurement. To minimize variations in temperature, mice were placed on a heating pad (37°C). The laser beam moved step by step in a rectangular pattern over the skin surface. The light penetrated the skin to a depth of 2 to 3 mm. In the presence of moving red blood cells in nutritional capillaries, arterioles, and venules, a fraction of the light is Doppler shifted, detected, and converted into a computerized, color-coded image. One measurement before treatment and one after 2 days of treatment were done with each mouse. Using image analysis software (Laser Doppler Perfusion measure, V3.0.8, Moor Instruments), mean flux values, representing the tumor perfusion, were calculated from the relative flux units.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging. This technique was used to assess changes in tumor perfusion and tracer penetration after 2 days of thalidomide treatment. Magnetic resonance imaging (MRI) was done with a 4.7-T (200 MHz, 1H) 40-cm inner diameter bore system (Bruker Biospec, Ettlingen, Germany). T2-weighted anatomic images were acquired using a fast spin-echo sequence (repetition time =3 seconds, effective echo time = 63 milliseconds]. A single, 1.3-mm-thick slice passing through the tumor center was prescribed. A birdcage radiofrequency coil with an inner diameter of 70 mm was used for radiofrequency transmission and reception. For dynamic contrast-enhanced MRI (DCE-MRI) studies, two slices were selected: one was centered on the kidneys and the other was positioned on the tumor. T1-weighted gradient-recalled echo images were obtained with the following parameters: repetition time = 40 milliseconds, effective echo time = 4.9 milliseconds, 1.6-mm slice thickness, flip angle =90°, matrix = 64 x 64, field of view = 6 cm, 25-kHz receiver bandwidth, resulting in an acquisition time of 2.56 seconds per scan. The DCE study was done using the following protocol. First, a set of 200 scans (8 minutes 32 seconds) was done dynamically. After the first 12 of these images had been acquired (for the baseline), P792 (Vistarem, Laboratoire Guerbet, Aulnay sous Bois, France) was given i.v. within 2 seconds (42 µmol/kg, 50 µL/30 g mouse). P792 (molecular weight, 6.47 kDa) is a monogadolinium macrocyclic compound based on a gadolinium-1,4,7,10-tetra-azacylododecane N,N',N',N'''-tetraacetic acid structure substituted by hydrophilic (dextran) arms. In this way, the signal intensity curve was therefore sampled to track the fast increase in tissue enhancement for viable tumor after the bolus injection. A second set of 60 images was then acquired over 1 hour to monitor the washout of the contrast agent. A calibration curve was generated with a Sephadex gel bead phantom (G-100, Pharmacia Fine Chemicals, Uppsala, Sweden) to convert signal enhancement into contrast agent concentration.
Kinetics Analysis. DCE-MRI raw data were zero-filled and two-dimensional Fourier transformed, resulting in an in-plane resolution of 128 x 128. An operator-defined region of interest encompassing the tumor was analyzed on a voxel-by-voxel basis to obtain parametric maps. A power spectrum analysis (28) was done to identify voxels with statistically significant variations in signal intensity. Among these voxels, only those for which the typical signal enhancement curve was observed were selected for the pharmacokinetic analysis (i.e., voxels showing either linear or no increase of signal intensity were discarded). This was done using a cluster analysis (28). Thereafter, the relative signal intensity enhancements (S/S0) were converted into P792 concentration (in millimoles per liter) using an equation generated by the in vitro calibration at 4.7T. The tumor P792 concentration versus time curves were analyzed by a two-compartment bidirectional pharmacokinetics model (29). The monoexponential decay rate of the contrast agent in the blood stream was estimated from the enhancement kinetics in the renal cortex. The concentration of the contrast agent in tumor contained contributions from the vascular and extravascular compartments and was fitted by using a four-parameter model: D0 (mmol/L), D1 (mmol/L/min), K2 (min–1), and t0 (min).
D0 is proportional to the plasma volume fraction and is related to the initial slope of the concentration-time curve:
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D1 is proportional to the rate of tracer accumulation in the interstitial space, and it determines the peak enhancement. If the blood supply is sufficient, D1 will depend on the permeability, total capillary surface area, and interstitial pressure.
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K2 is the fractional rate of efflux from the interstitial space back to the blood stream. t0 is the time to the maximum tracer plasma concentration. The time constant t0 was estimated individually for each mouse from the kidney data. Data fitting was done using Levenberg-Marquardt nonlinear least squares procedure. Parametric images were computed and only the statistically significant parameter estimates were displayed. Statistical significance for both D0 and D1, or only for D1, identified "perfused" voxels that displayed the typical signal curve enhancement on injection of the contrast agent injection.
IFP Measurement
IFP was measured using a "wick-in-needle" apparatus (30). An 18-gauge needle with a 1-mm side hole located at about 5 mm from the needle tip was connected to a pressure monitor system (295-1 Pressure, Stryker, Brussels, Belgium) specially designed for measuring tissue fluid pressures. The system was filled with saline water. A zero reference for the pressure system was done before each experiment and was reset by placing the needle beside the tumor. The skin was depilated the day before the experiment. Measurements were done by inserting the needle into the center of the tumor and injecting 50 µL of 0.9% sodium chloride to ensure fluid communication between the tumor and the pressure monitor system. During injection, the pressure rose by 30 to 50 mm Hg and rapidly decreased to a stable value. If the pressure remained elevated, rapidly dropped, or fluctuated, the value was discarded. Measurements were carried out after 2 days of treatment with thalidomide or vehicle. Acute nicotinamide delivery (500 mg/kg i.p. 120 minutes before the experiment) was used as a positive control (31).
Immunohistochemistry
FSAII tumor–bearing mice were sacrificed after 2 days of treatment with thalidomide (200 mg/kg) or vehicle. Tumor cryoslices were immunoprobed with rat monoclonal CD31 IgG2a antibodies (PharMingen, San Diego, CA). Rabbit polyclonal anti-rat IgG peroxidase-conjugated antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA) and AEC substrate system (DakoCytomation, Heverlee, Belgium) were used for revelation; sections were finally counterstained with Mayer's hematoxylin.
Irradiation and Tumor Regrowth Delay Assay
The tumor-bearing leg was locally irradiated with 20 Gy of 250-kV X-rays (RT 250, Philips Medical Systems, Hamburg, Germany). The tumor was centered in a 3-cm-diameter circular irradiation field. Different irradiation protocols were done: a single-dose irradiation of 20 Gy after intratumoral injection, a single-dose irradiation of 20 Gy after 2 days of treatment (i.p.), a single-dose irradiation of 20 Gy after 4 days of treatment (i.p.), and a single dose of 20 Gy followed by 2 days of treatment (i.p.). In each experiment, the treated group was compared with groups of mice receiving the vehicle (DMSO) alone, and DMSO + X-rays (RX). After treatment, tumor growth was determined daily by measuring transversal and anteroposterior tumor diameters until they reached a diameter of 16 mm, at which time the mice were sacrificed. A linear fit was obtained between 8 and 16 mm, which allowed us to determine the time to reach a particular size for each mouse.
Tumor Cell Culture
FSAII tumors in mice were dissected in a sterile environment and gently pieced in McCoy's medium. The cell suspension was filtered (100-µm pore size nylon filter, Millipore, Brussels, Belgium), centrifuged (5 minutes, 450 x g, 4°C), and cells were set to culture in DMEM containing 10% fetal bovine serum. Confluent cells were treated with thalidomide (100 µmol/L) or vehicle (DMSO) 1 hour before being irradiated at 2 Gy. To assess the cell radiosensitivity, trypan blue exclusion dye method and a clonogenic cell survival assay were done. For the former, the cells were counted for viability 24 hours after irradiation. For the latter, the cells were washed and reincubated in the conditioned medium without drug 24 hours after irradiation. After a 7-day incubation in a humidified 5% CO2 atmosphere at 37°C, the dishes were stained with crystal violet and colonies with >50 cells were counted.
Statistical Analysis
Results are given as means ± SE values from n animals. Comparisons between groups were made with Student's two-tailed t test and a P value <0.05 was considered significant. The GraphPad Prism 4.0 software was used for statistical analysis.
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RESULTS |
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Patent Blue Staining. A rough estimate of the tumor perfusion was carried out using the colored area observed in tumors after injection of a dye. Tumors with thalidomide treatment stained more positive (n = 4; 65.3 ± 8.7% ) than tumors treated with vehicle (n = 5; 38.4 ± 3.7%; Fig. 2A). This difference was found to be statistically significant (P < 0.05).
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Dynamic Contrast-Enhanced MRI. DCE-MRI was done to evaluate D0, D1, and K2 pharmacokinetic parameters in significantly enhancing voxels as determined by the cluster analysis. To take into account the maximal plasma P792 concentration (A0), the D0 and D1 values were divided by A0. Results are summarized in Fig. 3. The plasma volume fraction was significantly higher in the thalidomide group (n = 5) compared with the control mice (n = 4; P < 0.01). D1/A0, corresponding to the product of the volume fraction of extravascular extracellular space and the leakage rate, was higher in the thalidomide group than the control group, but this difference was not statistically significant (P > 0.05). The fractional efflux rate from interstitial space back to plasma (K2) was uniformly low in the control group in comparison with the thalidomide group (P < 0.05).
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Histologic Analysis
Immunohistologic staining with antibody directed against CD31 was used to investigate whether the tumor vascularization and organization were modified 2 days after thalidomide treatment. The examination of histologic sections by independent observers indicated that tumors were heterogeneous in their microvascular density. Vessels were uniformly distributed throughout the tumor for the control group compared with the treated group in which they were preferentially localized at the margin of the tumor with diameters substantially increased (Fig. 4). A decrease in the number of small vessels was also observed. Necrosis was present in both groups. Unexpectedly, thalidomide also modified tumor architecture, promoting heaps of tumor cells instead of being randomly distributed (Fig. 4).
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DISCUSSION |
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Our results showed an increase in tumor pO2 during the first 2 days of thalidomide treatment (Fig. 1) followed by a decrease in pO2. Such an increase in oxygen levels after antiangiogenic treatment had previously been reported by Lee et al. (12), Fenton et al. (33), and Teicher et al. (34–36). However, no oxygenation kinetic analysis was done in those studies. The decrease in tumor pO2 that we observed could be the result either of the antiangiogenic effect of thalidomide or a decrease in oxygen tension due to the tumor growth (11) as seen for the control group. Our observation of increased tumor oxygenation is likely the result of the ability of thalidomide to modify tumor microenvironment parameters such as the vascular supply and tumor perfusion. It has been shown that a short-term administration of antiangiogenic agents could prune inefficient vascular sprouts (8), leading to the establishment of more efficient flow paths. In fact, previous work has shown an increase in tumor oxygenation after antiangiogenic treatment despite a reduction in vascular density, indicating that the quality of vascular organization rather than the quantity of vessels determine tumor pO2 (12). This vascular stabilization could improve vascular function in the short term (8). Our histologic analysis reveals profound modifications in the vascular supply: a reduction in the number of tumor microvessels after thalidomide treatment together with a dilation of the remaining vessels with no decrease in the tumor vascular density (Fig. 4). The perfusion measured by DCE-MRI showed an increased plasma volume fraction (Fig. 3). This could be explained by the shift to larger blood vessel diameters as observed in histology analysis, perhaps due to compensation for the loss of small vessels (37). Patent Blue staining and laser Doppler imaging also showed an increase in tumor blood flow (Fig. 2A and B). The decrease in the tumor IFP could also explain the increase in perfusion and oxygenation by a mechanical effect: as the IFP decreases, there could be less pressure on tumor blood vessel walls, resulting in an increase in vascular diameter due to capillary compliance and lower geometric vascular resistance (38). As mentioned above, short-term administration of thalidomide induced a lowering of tumor IFP, probably resulting from the suppression of tumor immature blood vessels and from interstitial matrix remodeling. This decrease in IFP will then enhance transcapillary transport into the tumor interstitium because the interstitial pressure participates in the control of transcapillary fluid fluxes (8,39,40). DCE-MRI values of D1/A0 and K2, which reflect transcapillary flux, confirmed the increase in fluid flux into the tumor and into the vessel for the thalidomide group (Fig. 3).
The radiotherapy experiments showed the need to monitor the tumor microenvironment before planning combinations of treatments. In fact, thalidomide increased the radiosensitivity of FSAII tumor only after 2 days of treatment (Table 1). The other time windows showed no benefits. The radiosensitizing property of thalidomide can be attributed to the local increase in vascular supply of O2, as shown by EPR oximetry, because tumor cell cultures with thalidomide were not radiosensitized. These results are consistent with those obtained by Kinuya et al. (41) on other tumor cell types. Therefore, the regrowth delay observed is only due to the oxygen effect. An improvement in response to irradiation when antiangiogenic treatment is given has already been reported (12, 15–17, 35, 42–43), . However, in those studies, the increase in tumor oxygenation induced by antiangiogenic agents was not always reported as the cause of the radioresponse improvement. Our study showed that short-term thalidomide treatment before irradiation can improve vascular efficacy and oxygenation, which is the cause of the tumor regrowth delay observed. No effect of thalidomide alone on FSAII cell growth was observed (results not shown). This is consistent with previous in vitro experiments, which showed that thalidomide was unable to reduce proliferation of glioma cells (44) and was unable to exert direct cytotoxicity on LS180 cells (41). Moreover, no difference was observed between the tumor growth in control and thalidomide-treated mice. This failure toinhibit tumor growth has also been shown in other studies (45–47).
In conclusion, the study of changes in the tumor microenvironment during antiangiogenic drug treatment is of crucial importance for planning the combination of such drugs with radiation therapy. Our study reveals a short-term increase in tumor blood flow after thalidomide treatment. This could result, at least in part, from the normalization of tumor immature blood vessels. This normalization of the tumor vasculature decreased the tumor blood vessel resistance and tumor IFP. Consequently, the tumor pO2 was increased at the early phase of the thalidomide treatment. When irradiated at the time for which the maximal pO2 was observed, a radio sensitization was observed.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7/20/04; revised 9/30/04; accepted 10/ 6/04.
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, control group (n = 5); 
, thalidomide group (n = 8). Note the significant increase in pO2 at days 2 and 3 (*, P < 0.05) for treated group. Points, mean; bars, SE.
