Inhibition of mTOR suppresses experimental liver tumours.
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.
Rizell
Magnus
M
Department of Surgery, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. magnus.rizell@surgery.gu.se
Lindner
Per
P
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
D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus