title: Inhibition of mTOR suppresses experimental liver tumours.
abstract: Sirolimus, and its antiproliferative capacity, was studied in vivo in three different syngenic rat tumours in the liver. Sirolimus is an inhibitor of the cytosolic mTOR-kinase, associated with the phosphoinositide-3-kinase/Akt pathway. After one week of daily sirolimus treatment, initiated on the day of tumour-cell inoculation, a dose-response relationship was shown at doses between 0.01 mg/kg/day and 1 mg/kg/day, decreasing tumour weight from 0.5+/-0.1 g in control rats (n=9) to 0.09+/-0.04 g for sirolimus 1 mg/kg (n=9). Treating established liver adenocarcinoma (n=15), sirolimus halved the tumour weight (1.4+/-0.2 g vs 0.7+/-0.1 g, p=0.005). Trough concentration in blood was 6.4+/-0.2 ng/ml after five days of daily treatment with 1 mg/kg sirolimus intraperitoneally. At this dose, there was no decrease in food consumption or rat weight, but decrease in weight of spleen, and increase in weight of liver (p<0.01). The three tumours studied, an nitrosoguanidin-induced adenocarcinoma, a Leydig cell sarcoma and a hepatoma, all responded, establishing sirolimus as a promising anticancer drug.
authors.affiliation: Department of Surgery, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. magnus.rizell@surgery.gu.se
authors.forename: Magnus
authors.initials: M
authors.lastname: Rizell
authors.forename: Per
authors.initials: P
authors.lastname: Lindner
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D007984:Leydig Cell Tumor / Q000188:drug therapy / Q000201:enzymology; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011920:Rats, Inbred WF; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D013154:Spleen / Q000033:anatomy & histology; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus