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Nitrosoureas lomustine, carmustine and fotemustine induced hepatotoxic perturbations in rats: biochemical,
A Laquerriere1, G Raguenez-Viotte, M Paraire
1Laboratoire d'anatomo-pathologie et de cytologie pathologique, Hôpital Charles Nicolle, C.H.U., Rouen, France.
Abstract:
Chloroethylnitrosoureas are reactive compounds that are highly effective against malignant neoplasms in humans and animals. The most widely used nitrosoureas, lomustine and carmustine, are known to be hepatotoxic and to induce pericholangitis and intrahepatic cholestasis, which in the long term lead to cholangiolysis and biliary cirrhosis. However, the nitrosourea fotemustine has proved to be non-hepatotoxic at 20 mg/kg and 50 mg/kg. We have studied the effect of these three nitrosoureas on the cytotoxicity and cellular kinetics of rat liver cells. Lomustine and carmustine modify the proliferation index of liver cells in vivo: flow cytofluorometry showed that DNA cell distribution is quite similar for lomustine and carmustine, with subsequent accumulation of cells in G2 + M phase. 3 months later regressive morphological and cell cycle perturbations are noted for the lower dose of lomustine and carmustine. The most severe lesions are noted with lomustine (50 mg/kg). Fotemustine is not hepatotoxic and preferentially induces S phase perturbations. The more toxic nitrosoureas, lomustine and carmustine, induce comparable hepatocyte cell cycle alterations which differ from those induced by the less hepatotoxic nitrosourea fotemustine.
Insights
Chloroethylnitrosoureas like lomustine and carmustine are hepatotoxic, causing liver damage. Fotemustine, however, is non-hepatotoxic and affects liver cell cycles differently, offering a potentially safer alternative.
Area of Science:
- Hepatotoxicity and cellular kinetics of nitrosoureas
- Comparative analysis of anticancer drug effects on liver cells
Background:
- Chloroethylnitrosoureas are effective anticancer agents but lomustine and carmustine cause liver damage.
- Fotemustine demonstrates a lack of hepatotoxicity at therapeutic doses.
Purpose of the Study:
- To investigate the effects of lomustine, carmustine, and fotemustine on rat liver cell cytotoxicity and kinetics.
- To compare the cellular and morphological changes induced by these three nitrosoureas.
Main Methods:
- In vivo study of rat liver cells treated with lomustine, carmustine, and fotemustine.
- Flow cytofluorometry used to analyze DNA cell distribution and cell cycle phases.
- Morphological assessment of liver tissues at 3 months post-treatment.
Main Results:
- Lomustine and carmustine induced G2 + M phase cell cycle arrest and subsequent perturbations.
- Fotemustine preferentially induced S phase perturbations without significant hepatotoxicity.
- Higher doses of lomustine and carmustine resulted in more severe liver lesions.
Conclusions:
- Lomustine and carmustine induce similar, dose-dependent hepatocyte cell cycle alterations.
- Fotemustine exhibits a distinct, less toxic profile with preferential S phase effects.
- Fotemustine represents a potentially safer alternative to lomustine and carmustine regarding hepatotoxicity.
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