title: Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model.
abstract: 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 microg (n = 9) and 400 microg (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 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (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.
authors: Division of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Hua
authors: H
authors: Yan
authors: Cai
authors: C
authors: Cheng
authors: Amina
authors: A
authors: Haouala
authors: Thorsten
authors: T
authors: Krueger
authors: Jean-Pierre
authors: JP
authors: Ballini
authors: Solange
authors: S
authors: Peters
authors: Laurent A
authors: LA
authors: Decosterd
authors: Igor
authors: I
authors: Letovanec
authors: Hans-Beat
authors: HB
authors: Ris
authors: Snezana
authors: S
authors: Andrejevic-Blant
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D011336:Probability; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D012680:Sensitivity and Specificity
chemical_list: D008081:Liposomes; D004317:Doxorubicin