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±0.1g in control rats (n=9) to 0.09±0.04g for sirolimus 1 mg/kg (n=9). Treating established liver adenocarcinoma (n=15), sirolimus halved the tumour weight (1.4±0.2g vs 0.7±01g, 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 Leydic cell sarcoma and a hepatoma, all responded, establishing sirolimus as a promising anticancer drug.
Footnotes
- Received September 23, 2004.
- Revision received December 27, 2004.
- Accepted February 4, 2005.
- Copyright© 2005 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved