title: Hepatic arterial infusion of temsirolimus inhibits tumor growth of colorectal rat liver metastases even after a growth stimulating procedure like liver resection.
abstract: BACKGROUND
  Hepatic arterial infusion (HAI) of specific anti-tumor drugs can be more effective compared with systemic drug application. Herein, we studied whether HAI of temsirolimus is effective to inhibit tumor growth of colorectal liver metastases after liver resection.
  
  
  METHODS
  Twenty-four Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats were randomized to four groups and underwent subcapsular implantation of CC531 colorectal cancer cells in the left liver lobe. In two groups, a 70% liver resection (Phx) was performed simultaneously. After 10 d, animals received either a HAI of temsirolimus (CCI-779) or saline solution (controls). Tumor growth was determined on d 10 and 13 using three-dimensional ultrasound. On d 13, tumor tissue was removed for histologic and immunohistochemical analysis.
  
  
  RESULTS
  Sham controls revealed a tumor growth of ∼40% from d 10 to d 13. HAI of temsirolimus completely inhibited this tumor growth. Controls with Phx showed a tumor growth of >60%. In contrast, HAI of temsirolimus in Phx animals did not only inhibit tumor growth but was even capable of decreasing the tumor size by ∼8%. Immunohistochemical analysis of the tumors showed a decreased proliferation rate and an increased cleaved caspase-3 activity, which was associated with a significant reduction of platelet endothelial cell adhesion molecule (PECAM)-1-positive cells after HAI of temsirolimus.
  
  
  CONCLUSIONS
  HAI of temsirolimus inhibits tumor growth of CC531 colorectal liver metastases even if a growth-stimulating procedure like Phx is performed. Inhibition of tumor growth is provided by a decrease of tumor vascularization associated with an inhibition of tumor cell proliferation and an induction of tumor cell apoptosis.
authors.affiliation: Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany; Department of General, Visceral and Pediatric Surgery, University Medical Center, Georg August University, Göttingen, Germany. Electronic address: jens.sperling@med.uni-goettingen.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Sperling
authors.forename: Christian
authors.initials: C
authors.lastname: Ziemann
authors.forename: Anika
authors.initials: A
authors.lastname: Gittler
authors.forename: Anna
authors.initials: A
authors.lastname: Benz-Weißer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Otto
authors.initials: O
authors.lastname: Kollmar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D006499:Hepatic Artery; D008099:Liver / Q000601:surgery*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus
keywords: Apoptosis; Colorectal liver metastases; Hepatic arterial infusion; Proliferation; Temsirolimus; Vascularization