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Original Articles: General Thoracic

Distribution of Free and Liposomal Doxorubicin After Isolated Lung Perfusion in a Sarcoma Model

^a Division of Thoracic Surgery, Swiss Federal Institute of Technology, Lausanne, Switzerland
^b Division of Clinical Pharmacology and Toxicology, Swiss Federal Institute of Technology, Lausanne, Switzerland
^d Division of Oncology, Swiss Federal Institute of Technology, Lausanne, Switzerland
^e Division of Pathology, Centre Hospitalier Universitaire Vaudois, Swiss Federal Institute of Technology, Lausanne, Switzerland
^c Institute of Environmental Engineering, Swiss Federal Institute of Technology, Lausanne, Switzerland

Accepted for publication December 10, 2007.

^_* Address correspondence to Dr Ris, Service de Chirurgie Thoracique et Vasculaire, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne, 1011, Switzerland (Email: hans-beat.ris{at}chuv.ch).

Background: Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor.

Methods: A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 µg (n = 9) and 400 µg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors.

Results: The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 µg (0.27 ± 0.1 vs 0.53 ± 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 µg (0.67 ± 0.2 vs 0.54 ± 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed.

Conclusions: Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.