title: Tumour growth of colorectal rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation.
abstract: Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5×10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL.
authors.affiliation: Institute for Clinical and Experimental Surgery, University of Saarland, Homburg, Saarland, Germany, 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; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D007261:Infusions, Intra-Arterial; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011169:Portal Vein / Q000601:surgery*; D011897:Random Allocation; D051381:Rats; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C401859:temsirolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D020123:Sirolimus