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Ann Thorac Surg 2006;82:2024-2030
© 2006 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Antegrade Versus Retrograde Isolated Lung Perfusion: Doxorubicin Uptake and Distribution in a Sarcoma Model

Thorsten Krueger, MDa,*, Andrea Kuemmerle, PhDb, Snezana Andrejevic-Blant, MDc, Hua Yan, MDa, Youmin Pan, MDa, Jean-Pierre Ballini, PhDd, Walter Klepetko, MDe, Laurent Arthur Decosterd, PhDb, Roger Stupp, MDb, Hans-Beat Ris, MDa

a Division of Thoracic Surgery, Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland
b Division of Clinical Pharmacology and Toxicology, Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland
c Institute of Pathology, Multidisciplinary Oncology Center, University Hospital, Lausanne, Switzerland
d Air and Soil Pollution Laboratory, Swiss Federal Institute of Technology, Lausanne, Switzerland
e Department of Cardiothoracic Surgery, University Hospital, Vienna, Austria

Accepted for publication May 11, 2006.

* Address correspondence to Dr Krueger, Service de Chirurgie Thoracique et Vasculaire, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, CH 1011 Lausanne, Switzerland (Email: thorsten.krueger{at}chuv.ch).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Antegrade and retrograde doxorubicin-based isolated lung perfusions were compared in rodents bearing a sarcomatous tumor in the perfused lung. Inasmuch as these tumors derive their vascularization from the bronchial artery system, we hypothesized that retrograde isolated lung perfusion through the pulmonary vein might result in an improved tumor drug uptake.

METHODS: Single-pass antegrade (n = 9) and retrograde (n = 9) isolated left lung perfusions were performed with 100 µg of doxorubicin in Fischer rats 10 days after subpleural tumor cell injection. The perfusion, washout, and recirculation times were 20, 10, and 60 minutes, respectively, followed by harvesting of the lung. The doxorubicin concentration and compartmental distribution in the tumor and in normal parenchyma of each perfused lung were measured by high-pressure liquid chromatography (6 animals of each group) and fluorescence microscopy (3 animals of each group).

RESULTS: Doxorubicin concentration and pattern of doxorubicin-based fluorescence signaling were comparable for both perfusion techniques in normal lung tissue. Antegrade and retrograde isolated lung perfusion resulted in similar tumor drug uptake, which was lower than in normal lung parenchyma, and in weak and sporadic fluorescence signaling emerging from the tumor periphery and from blood vessels situated within the tumor tissue.

CONCLUSIONS: Retrograde isolated lung perfusion did not confer a better doxorubicin uptake in the tumor as compared with antegrade lung perfusion despite the fact that the tumor vascularization in this model is based on the bronchial artery circulation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cytostatic isolated lung perfusion (ILP) is an attractive treatment concept because it allows an organ-specific delivery of the agent while sparing the systemic circulation. This may result in an enhanced drug concentration in the target organ with reduced systemic side effects. It has been assessed for the treatment of pulmonary metastases under clinical conditions [1–8] and refined in experimental settings [9–15]. Indeed, ILP has shown an up to sevenfold higher drug concentration in lung tissue and significantly lower plasma levels as compared with intravenous application of an equivalent dose of cytostatic drug [14, 15]. However, ILP has not yet achieved a clinically relevant antitumor activity, irrespective of the cytostatic agent administered. Moreover, several studies suggest a lower drug uptake in tumors than in the surrounding normal lung tissue after ILP [1, 2, 5].

Recently, a study in sheep has explored the possibility of retrograde paclitaxel- based ILP combined with hyperthermia, and has demonstrated its feasibility and a substantial pharmacokinetic advantage as compared with intravenous administration [16]. Inasmuch as the lung comprises two arterial blood supplies (pulmonary and bronchial arteries) that drain into a common venous system, retrograde ILP through the pulmonary vein (PV) has the theoretical advantage of perfusing both the pulmonary and bronchial artery territories. In contrast, antegrade ILP through the pulmonary artery (PA) as used in most settings so far does not take into account the bronchial artery territory. Retrograde ILP might therefore result in a more homogeneous drug uptake of the perfused lung, and in drug delivery to tumor deposits that derive their blood supply from bronchial arteries [17–20].

In this study, we compared antegrade and retrograde doxorubicin-based ILP in rodents with a sarcomatous lung tumor with respect to uptake and distribution of the perfused drug in the tumor and surrounding normal lung parenchyma.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Design
Single-pass, gravity-driven ILP of the left lung was performed with 100 µg of doxorubicin in 18 animals bearing a single sarcoma tumor in their left lung. Tumor generation was performed by subpleural injection of a sarcoma cell suspension 10 days before antegrade ILP (n = 9) and retrograde ILP (n = 9). The doxorubicin concentration and compartmental distribution in the tumor and in normal surrounding parenchyma of each perfused lung were measured by high-pressure liquid chromatography (6 animals of each group) and fluorescence microscopy (3 animals of each group), respectively.

Animals and Housing
Male Fischer 344 rats, weighting 250–300g (Charles River, L’Arbresle, Cedex, France) were used. They had free access to standard laboratory rat chow and water and were housed with a 12-hour light–12-hour dark circle under controlled temperature. They were treated in accordance with the animal welfare act, the national guidelines for the care and use of laboratory animals, and according to the Local Ethical Committee of the University of Lausanne.

Tumor Cell Line
A syngeneic methylcholanthrene-induced sarcoma cell line kindly supplied by the Memorial Sloan-Kettering Cancer Center (New York, NY) was used [21]. The methylcholanthrene-induced sarcoma cell line was cultivated at 37°C and 5% CO2 in 20 mL of RPMI-1640 medium containing glutarate, 10% fetal bovine serum, and 1% penicillin–streptomycin (Invitrogen Corporation, GIBCO Life Technologies Ltd, UK). For the preparation of the cell suspension, the cells were washed twice with phosphate-buffered saline solution and detached with 4 mL of trypsin. Tumor cell vitality was assessed in a hematocytometer after centrifugation at 1,000 g for 4 minutes, washing, resuspension in phosphate-buffered saline solution, and addition of trypan blue. The cell suspension was adjusted to a density of 5.0 x 106 vital cells/mL.

Generation of Sarcoma Tumors Within the Left Lung
Anesthesia was induced by intraperitoneal injection of pentobarbital sodium (50 mg/kg) and 0.1% atropine (0.05 mL/kg). Orotracheal intubation was performed by tracheal insertion of a 16-gauge polyethylene Angiocath (Becton Dickinson, Sandy, UT) using a laryngoscope. The catheter was connected to a standard rodent ventilator (model 683, Harvard Apparatus, Inc, France), and ventilation was performed with a mixture of oxygen and isoflurane (0.5% to 2%; Forene, Abbott, Switzerland). A tidal volume of 10 mL/kg was adjusted with a respiratory rate of 75 to 90 breaths/min. A small left-sided thoracotomy was performed through the seventh intercostal space. One tenth of a milliliter of methylcholanthrene-induced sarcoma cell solution containing 5.0 x 106 viable tumor cells was injected subpleurally into the left lower lobe by use of a 27-gauge needle and a 0.3-mL insulin syringe [22]. The thoracotomy was closed in layers, and the endotracheal tube was removed after the animals began breathing spontaneously.

Technique of Antegrade and Retrograde Isolated Lung Perfusion of the Left Lung
Ten days after tumor implantation, single-pass ILP with doxorubicin (Adriblastin, Pharmacia & Upjohn, Dübendorf, Switzerland) of the left lung was performed. The animals were anesthetized as described above. A left-sided thoracotomy was performed through the fourth intercostal space. An operative microscope was used (magnification, x16; Zeiss, Jena, Germany). The inferior pulmonary ligament was divided, and the left lung was retracted anteriorly. The mediastinal pleura was opened while the bronchial arteries and the left phrenic nerve were preserved. The left PA and PV were dissected. The vessels were encircled by use of 8-0 Prolene sutures (Johnson and Johnson Medical, Spreitenbach, Switzerland) and clamped. Small transverse incisions were performed in the PA and PV distal to the clamps using microvascular scissors, and both vessels were cannulated by use of two catheters consisting of a 2-cm polyethylene tube, 0.10 mm ID, 0.30 mm OD, connected to a 20-cm polyethylene tube, 0.30 mm ID, 0.60 mm OD (Clinical Plastic Products SA, La Chaux-de-Fonds, Switzerland). Single-pass ILP with 100 µg of doxorubicin dissolved in 5 mL of 6% hydroxyethyl starch was performed during 20 minutes using a roller pump at a flow rate of 0.25 mL/min. The concentration of doxorubicin in the perfusate was 20 µg/mL.

Antegrade ILP consisted of drug administration through the PA and effluent collection from the PV. Retrograde ILP consisted of drug delivery through the PV and effluent collection from the PA.

The cytostatic perfusion was followed by a washout phase of the ILP for 10 minutes with 5 mL of 6% hydroxyethyl starch at the same perfusion conditions. The lung was ventilated during ILP with a positive end-expiratory pressure of 2 to 3 cm H2O. After completion of ILP, the catheters were removed and the vessels were repaired by interrupted transverse sutures using Prolene 10-0 followed by removal of clamps and restoration of the circulation. Ventilation with a positive end-expiratory pressure of 2 to 3 cm H2O was continued for 60 minutes after restoration of the circulation. At this point, the animals were sacrificed and the perfused lung was harvested.

Assessment of Doxorubicin Concentration in Tumor and Healthy Lung Tissue
After harvesting of the perfused lungs, the tumor nodule was dissected from the surrounding normal lung tissue of the lower lobe by use of the operation microscope, and tumor and normal tissue of the lower lobe were analyzed separately. The samples were kept on ice and stored at –80°C before analysis. Doxorubicin concentration measurements in tissues were performed by high-pressure liquid chromatography as previously described [23].

Assessment of Drug Distribution in Tumor and Healthy Lung Tissues by Fluorescence Microscopy
The perfused lungs were harvested, snap-frozen in liquid nitrogen by contact with isopentane slush, stored at –70°C, and processed for fluorescence microscopy as previously described [24]. The frozen tissue blocks were mounted in OCT medium (Tissue Tek II embedding compound, BDH, Switzerland), and a series of sections was cut with a cryomicrotome (Frigocut Model 2700, Reichert, Switzerland). Six consecutive, nonstained 5-µm-thick tissue sections mounted on clean glass slides were prepared for each sample. From each frozen section, three images were recorded over three different parts of the slice to avoid photobleaching. We used a Zeiss AxioPlan-2 microscope equipped with a Zeiss Axiophot image analysis system (Zeiss, Switzerland) and a filtered 100-W mercury lamp as the excitation light source. Images were recorded with a gray-scale camera with a 12-bits dynamic range and 2 x 2 binning, resulting in 694 x 520 pixel images with 4,095 gray levels. A filter "cube" (set 40012, Chroma Technology Corp, Rockingham, VT; excitation, HQ 480/40x; dichotic mirror, Q505LP) and a barrier filter (HQ510LP) have been used for epifluorescence measurements. After recording the fluorescence images, the same slices were stained with hematoxylin and eosin. A hematoxylin and eosin–stained image was recorded from the identical position and compared with the fluorescence image to determine the histologic localization of doxorubicin using the public domain Image J 1.31 program (National Institutes of Health, Bethesda, MD). This technique allows the detection of the fluorescence signaling of doxorubicin in different tissue compartments of normal lung parenchyma and within the tumor.

Statistical Analysis
Doxorubicin concentrations in tumors and normal lung parenchyma were compared for both ILP techniques using Student’s t test for unrelated samples. A bidirectional hypothesis was applied, and significance was accepted at probability values less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
All 18 animals underwent successful tumor implantation and antegrade or retrograde left-sided doxorubicin-based ILP. There was no difference between perfusion techniques with respect to postoperative recovery.

Histologic assessment of the tumors revealed a well-circumscribed sarcomatous tumor in each left lung, mainly formed by large undifferentiated cells with a vascular network consisting of fine branching capillaries present throughout the tumor. The tumor size ranged from 3 to 8 mm in diameter with an approximate volume ranging from 90 to 500 mm3. The mitotic index ranged from 12 to greater than 100 mitoses per 10 high-power fields (surface, 0.221 mm3/field). Spontaneous necrosis was observed in less than 2% of the tumor volume for each case analyzed. No spread within the pleural cavity was identified in any animal assessed.

Doxorubicin Concentration in Tumor and Normal Lung Parenchyma After Isolated Lung Perfusion
Tables 1 and 2 Go show the doxorubicin concentrations in the tumor and healthy lung parenchyma after antegrade and retrograde doxorubicin-based ILP. There was a wide interanimal variability of drug concentrations in the tumor and normal lung tissue, and of the ratio of tumor to normal tissue drug concentration, for both perfusion techniques applied. In all animals, there was a lower drug concentration in the tumor as compared with normal lung parenchyma, irrespective of the perfusion technique applied. The mean doxorubicin concentration in the tumor and normal lung tissue did not differ significantly between both perfusion techniques. The ratio of tumor to normal tissue drug concentration was not significantly different for antegrade or retrograde ILP.


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  		Table 1. Doxorubicin Concentration in Perfused Lung Tissue and in Tumor After Antegrade Isolated Lung Perfusion in Rodents Bearing a Sarcoma Tumor in Their Left Lung
 

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  		Table 2. Doxorubicin Concentration in Perfused Lung Tissue and in Tumor After Retrograde Isolated Lung Perfusion in Rodents Bearing a Sarcoma Tumor in Their Left Lung
 
Doxorubicin Distribution in Tumor and Normal Lung Parenchyma After Isolated Lung Perfusion
Fluorescence microscopy revealed doxorubicin fluorescence signaling exclusively confined to the nuclei of the cells of normal lung parenchyma and tumor tissue. This was found in all perfused lungs whatever the tissue or cell type observed. Both perfusion techniques resulted in similar fluorescence signaling emerging from all tissue compartments of normal lung parenchyma, including pneumocytes of the alveolar wall, endothelial cells of blood vessels, bronchial epithelium, and mesothelial cells covering the parietal pleura, without differences between the perfusion techniques (Fig 1). In contrast, antegrade and retrograde ILP resulted both in weak and sporadic fluorescence signaling emerging from tumors that was mainly confined to the tumor periphery, to peritumoral inflammatory cells, and to blood vessels situated within the tumor tissue (Fig 2). Central and nonvascularized parts of the tumor did not show fluorescence signaling in all perfused lungs assessed, irrespective of the perfusion technique applied.


Figure 1
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  		Fig 1. Fluorescence signaling of doxorubicin after isolated lung perfusion emerging from all tissue compartments of normal lung parenchyma including pneumocytes of the alveolar wall, endothelial cells of blood vessels, and bronchial epithelium, without differences between the perfusion techniques: fluorescence photomicrograph (A) and corresponding hematoxylin and eosin stain (B) after antegrade isolated lung perfusion; fluorescence photomicrograph (C) and corresponding hematoxylin and eosin stain (D) after retrograde isolated lung perfusion. Original magnification, x 400. (B = bronchi; LP = lung parenchyma-alveolar wall; V = blood vessel.)

 

Figure 2
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  		Fig 2. Weak and sporadic fluorescence signaling of doxorubicin after isolated lung perfusion emerging from the tumor confined to the tumor periphery (arrow) and small tumor blood vessels (V), irrespective of the perfusion technique applied: fluorescence photomicrograph (A) and corresponding hematoxylin and eosin stain (B) after antegrade isolated lung perfusion; fluorescence photomicrograph (C) and corresponding hematoxylin and eosin stain (D) after retrograde isolated lung perfusion. Original magnification, x 400.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Cytostatic ILP was assessed under clinical and experimental conditions for various agents including doxorubicin [1, 2, 5, 10–15], melphalan [8], platinum [3, 6], and tumor necrosis factor-{alpha} combined with interferon-{gamma} [4]. All trials have demonstrated excellent separation between systemic and pulmonary circulations with minimal or undetectable systemic drug levels. Isolated lung perfusion resulted in acceptable toxicity in patients and effectively delivered high doses of the cytostatic agent to the perfused lung. However, the clinical response was suboptimal in those trials in which no metastasectomy was performed. Effective shielding of the tumor tissue from the delivered drug or uneven drug distribution within the perfused lung may be responsible for these disappointing results after cytostatic ILP in patients. Indeed, clinical and experimental work has shown that although the overall uptake of doxorubicin was up to seven times higher in the lung parenchyma than in the systemic circulation during ILP [14, 15], the tumor drug uptake was generally lower than that measured in tumor-free lung tissues [1, 2, 5].

The source of tumor vascularization may be one explanation for a lower drug uptake in tumor than in normal lung tissue during ILP. Because the lung has two arterial blood supplies (the pulmonary and bronchial artery systems), which drain into a common venous system, antegrade ILP with drug delivery through the PA bears the risk of insufficient irrigation of the bronchial artery territories. Tumors deriving their blood supply from the bronchial artery circulation may therefore be shielded from sufficient drug delivery. Clinical and experimental studies have shown that primary pulmonary neoplasms and metastases may derive their blood supply from both vascular territories. Centrally located metastases tended to derive their blood supply from the bronchial arteries, whereas peripheral metastases usually were supplied by the PA circulation [17–20]. Retrograde ILP with drug delivery through the PVs has the advantage of perfusing both the pulmonary and bronchial artery territories and should theoretically result in a better drug uptake in tumors deriving their blood supply (in part or entirely) from the bronchial arteries.

This experimental study was designed to assess whether retrograde doxorubicin-based ILP resulted in enhanced tumor drug uptake as compared with antegrade ILP. Doxorubicin-based single-pass ILP was assessed in rodents bearing a syngeneic methylcholanthrene-induced sarcomatous (MCA) tumor. This model has been investigated in the context of experimental ILP and has demonstrated a high drug uptake in lung tissue with minimal systemic toxicity. However, tumor generation has been obtained by intravenous tumor cell injection in those experiments [9–13]. Recently, we have compared the blood supply of sarcomatous tumors growing in rat lungs after intravenous or direct subpleural tumor cell injection, and have shown that in this tumor model, the tumor blood supply critically depended on the route of tumor injection. Tumors generated by subpleural injection derived their blood supply from the bronchial artery and intravenously generated tumors from the PA circulation [22]. Because in this experimental setting the tumors were generated by subpleural tumor cell injection with their blood supply emerging from the bronchial artery system, we hypothesized that retrograde ILP should result in an increased tumor drug uptake as compared with antegrade ILP.

The doxorubicin uptake and distribution within the tumors and the surrounding lung parenchyma after ILP was measured by high-pressure liquid chromatography and fluorescence microscopy, respectively. The native fluorescence properties of doxorubicin allow its localization in different compartments by recording the fluorescence signaling and superposing the fluorescence images on conventional hematoxylin and eosin–staining of identical slices.

Our results demonstrated that both perfusion techniques resulted in a similar and not significantly different doxorubicin uptake in the parenchyma of the perfused lungs. All compartments of normal lung parenchyma, including all components of the bronchial wall, revealed doxorubicin fluorescence signaling, irrespective of the perfusion technique applied. We also found for both perfusion techniques a similar and not significantly different doxorubicin tumor uptake, which was lower than that in surrounding parenchyma for all animals assessed. Romijn and colleagues [25] showed in a similar rat model that retrograde ILP increased cytostatic drug concentration in hilar and basal regions of the perfused lung compared with antegrade ILP. Although the tumor was generated in the lower lobe of the perfused lung in our setting, our results did not endorse the findings of this recently published study. This may be related to the large interanimal variability of doxorubicin concentrations in the perfused lungs that was observed with both perfusion techniques.

Antegrade and retrograde ILP resulted both in weak and sporadic fluorescence signaling emerging from tumors, which was mainly confined to the tumor periphery, to peritumoral inflammatory cells, and to blood vessels situated within the tumor tissue. Central and nonvascularized parts of the tumor did not show fluorescence signaling in all perfused lungs assessed, irrespective of the perfusion technique applied. We speculate that the poor penetration of doxorubicin into the tumors might be related to a direct drug–tumor interaction at the level of the tumor vessel rather than to a breakdown or insufficient development of the microcirculation, which may be observed in growing tumors. Histologic assessment of the tumors revealed a vascular network consisting of fine branching capillaries present throughout the tumor and less than 2% spontaneous necrosis of the tumor volume for each case analyzed. Moreover, fluorescence microscopic assessment of the perfused tumors revealed a clear-cut difference in doxorubicin signaling that was confined to the vessel wall of the vessels situated within the tumors and absent in tumor cells adjacent to those vessels (Fig 2).

In conclusion, our results demonstrated that in this experimental setting, antegrade and retrograde ILP resulted in similar doxorubicin uptake and distribution in the perfused lung, and in an equally weak tumor penetration of doxorubicin that was mainly confined to the tumor periphery and small tumor vessels. Despite the fact that these tumors derived their vasculature from the bronchial artery system, retrograde ILP did not yield a better ratio of tumor to normal tissue drug concentration than antegrade ILP. Further efforts should be directed to alleviate the poor tumor penetration after doxorubicin-based ILP, eg, by inducing a selective enhancement of the tumor vessel permeability at the level of the endothelial barrier [26].


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The Swiss National Science Foundation (No. 3200–59550) and the Fondation Andreas P. Naef pour la Chirurgie Thoracique have supported this study.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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