title: Isolated lung perfusion as an adjuvant treatment of colorectal cancer lung metastases: a preclinical study in a pig model.
abstract: BACKGROUND
  The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP.
  
  
  METHODS
  First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria.
  
  
  RESULTS
  In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent.
  
  
  CONCLUSIONS
  GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.
authors.affiliation: INSERM UMR 866, CHU Bocage, University of Burgundy, Dijon, France. pb.pages@live.fr
authors.forename: Pierre-Benoit
authors.initials: PB
authors.lastname: Pagès
authors.forename: Olivier
authors.initials: O
authors.lastname: Facy
authors.forename: Pierre
authors.initials: P
authors.lastname: Mordant
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Guy
authors.initials: G
authors.lastname: Magnin
authors.forename: Francois
authors.initials: F
authors.lastname: Lokiec
authors.forename: Francois
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D015179:Colorectal Neoplasms / Q000473:pathology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D010477:Perfusion / Q000379:methods*; D013552:Swine; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000093542:Gemcitabine