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Inhibition of mTOR suppresses experimental liver tumours

Magnus Rizell1, Per Lindner

  • 1Department of Surgery, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. magnus.rizell@surgery.gu.se

Anticancer Research
|May 5, 2005
PubMed

Insights

Sirolimus effectively reduced liver tumor weight in rats, showing a dose-response relationship. This mTOR inhibitor holds promise as an anticancer drug, with no adverse effects on food intake or body weight.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Sirolimus (rapamycin) is a known inhibitor of the mechanistic target of rapamycin (mTOR) kinase.
  • The mTOR pathway is closely linked to the phosphoinositide-3-kinase/Akt signaling cascade, which plays a critical role in cell growth and proliferation.
  • Dysregulation of the mTOR pathway is implicated in various cancers, making it a target for therapeutic intervention.

Purpose of the Study:

  • To investigate the in vivo antiproliferative capacity of sirolimus against syngenic rat liver tumors.
  • To establish a dose-response relationship for sirolimus treatment in reducing tumor weight.
  • To evaluate the efficacy of sirolimus in established liver adenocarcinoma models.

Main Methods:

  • Daily intraperitoneal administration of sirolimus to rats bearing three different syngenic liver tumors.
  • Dose-ranging studies were conducted from 0.01 mg/kg/day to 1 mg/kg/day.
  • Tumor weight, food consumption, body weight, spleen weight, and liver weight were measured. Blood trough concentrations of sirolimus were determined.

Main Results:

  • Sirolimus demonstrated a significant dose-dependent reduction in tumor weight, from 0.5+/-0.1 g in controls to 0.09+/-0.04 g at 1 mg/kg/day.
  • In established liver adenocarcinoma, sirolimus treatment halved tumor weight (1.4+/-0.2 g vs 0.7+/-0.1 g, p=0.005).
  • A dose of 1 mg/kg/day resulted in a blood trough concentration of 6.4+/-0.2 ng/ml without affecting food intake or body weight, but decreased spleen weight and increased liver weight.

Conclusions:

  • Sirolimus exhibits potent in vivo antiproliferative activity against multiple syngenic rat liver tumors, including adenocarcinoma, Leydig cell sarcoma, and hepatoma.
  • The drug establishes a clear dose-response relationship and is effective in both early-stage and established tumors.
  • Sirolimus is a promising anticancer drug candidate, warranting further investigation for clinical application.

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