Rapamycin
- also called sirolimus, marketed as RapamuneŽ by Wyeth
Mammalian
target of rapamycin, or mTOR, is an enzyme involved in regulating cell division.
Studies have shown that the mTOR signaling pathway plays a key role in the activation
of hepatic stellate cells, which produce extracellular matrix (ECM); excessive
production and accumulation of ECM causes liver fibrosis.
As
described in the December 2006 Journal of Hepatology, Swiss researchers
conducted an animal study to assess the therapeutic potential of the mTOR inhibitor
rapamycin, an immunosuppressive drug better known as sirolimus (Rapamune).
The
study involved rats with advanced liver cirrhosis artificially induced by bile
duct ligation or thioacetamide injections. Some of the rats received oral rapamycin
(0.5mg/kg/day) for 14 or 28 days, while untreated rats served as controls.
The
investigators quantified liver function (using the aminopyrine breath test and
the presence of ECM and ECM-producing cells. They also measured matrix metalloproteinase
2 (MMP-2) activity, messenger RNA (mRNA) expression of procollagen-alpha1, transforming
growth factor-beta1 (TGF-beta1) and TGF-beta2.
Results
•
Liver function improved
after the rats received rapamycin for 14 days.
•
Accumulation of ECM
was decreased, together with numbers of activated hepatic stellate cells and MMP-2
activity.
•
TGF-beta1 mRNA was
down-regulated in rats that received thioacetamide injections, while TGF-beta2
mRNA was down-regulated in animals that underwent bile duct ligation.
•
28 days of rapamycin
treatment was associated with a survival advantage in the bile duct ligation rats.
Conclusion
"Low-dose
rapamycin treatment is effectively anti-fibrotic and attenuates disease progression
in advanced fibrosis,"
the authors concluded. "Our results warrant the clinical evaluation of rapamycin
as an anti-fibrotic drug."
1/12/07
Reference M
Neef, M Ledermann, H Saegesser, and others. Low-dose oral rapamycin treatment
reduces fibrogenesis, improves liver function. Journal of Hepatology 45(6):
786-796. December 2006.
