title: Selective pulmonary artery perfusion followed by blood flow occlusion: new challenge for the treatment of pulmonary malignancies.
abstract: BACKGROUND
  Selective pulmonary artery perfusion (SPAP) is an experimental endovascular technique for the treatment of pulmonary malignancies. This study evaluated blood flow occlusion (BFO) after SPAP and dose-escalation in order to delay washout of gemcitabine from the lung tissue, to augment pulmonary drug exposure and to maintain plasma concentrations equivalent to intravenous administration.
  
  
  METHODS
  Six groups of pigs underwent left-sided SPAP using gemcitabine in a clinically applied dose of 1-1.5g/m(2) after balloon catheterisation. BFO experiment: four groups (n=4, each) were treated with SPAP with 1g/m(2) of gemcitabine during 2 min followed by BFO for 0, 10, 20 and 30 min, respectively. Dose-escalation experiment: two more groups (n=3, each) received SPAP with 1.25 and 1.5 g/m(2) of gemcitabine during 2 min followed by 30 min BFO. All pigs underwent left thoracotomy with sampling of lung, liver and blood. The animals were sacrificed after 1h. The lung and plasma areas under the curve (AUC) were calculated for each group and ANOVA and t-test was used for comparison.
  
  
  RESULTS
  Thirty minutes BFO resulted in the highest lung AUC compared to 0, 10 and 20 min BFO (p<0.001), while no significant differences in plasma AUC and liver levels were observed. Gemcitabine dose-escalation up to 1.25 g/m(2) resulted in significantly higher lung AUC (p=0.02) compared to 1g/m(2), while plasma AUC was equivalent with intravenous treatment. Further dose-escalation to 1.5g/m(2) did not result in significantly higher lung levels compared to 1.25 g/m(2).
  
  
  CONCLUSIONS
  BFO after SPAP delays the washout of gemcitabine from lung tissue. Dose-escalation resulted in higher lung concentrations, while plasma levels were equivalent with intravenous administration. We advocate 2 min of SPAP with 1.25 g/m(2) of gemcitabine followed by 30 min of BFO to be investigated as a new treatment modality for pulmonary malignancies.
authors.affiliation: Department of Pulmonary Medicine, Antonius Hospital, Nieuwegein, The Netherlands. mgrootenboers@amphia.nl
authors.forename: Marco J J H
authors.initials: MJ
authors.lastname: Grootenboers
authors.forename: Franz M N H
authors.initials: FM
authors.lastname: Schramel
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Boven
authors.forename: Jeroen M H
authors.initials: JM
authors.lastname: Hendriks
authors.forename: Paul E Y
authors.initials: PE
authors.lastname: van Schil
authors.forename: Peter E J
authors.initials: PE
authors.lastname: De Wit
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.forename: Bart P
authors.initials: BP
authors.lastname: van Putte
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D002404:Catheterization; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004621:Embolization, Therapeutic / Q000379:methods*; D005260:Female; D007261:Infusions, Intra-Arterial; D008175:Lung Neoplasms / Q000098:blood supply / Q000628:therapy*; D009374:Neoplasms, Experimental; D010477:Perfusion / Q000379:methods*; D011651:Pulmonary Artery; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013552:Swine; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine