Laquerriere A, Raguenez-Viotte G, Paraire M, Bizzari J P, Paresy M, Fillastre J P, Hemet J
Laboratoire d'anatomo-pathologie et de cytologie pathologique, Hôpital Charles Nicolle, C.H.U., Rouen, France.
Eur J Cancer. 1991;27(5):630-8. doi: 10.1016/0277-5379(91)90232-3.
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.
氯乙基亚硝脲是一类活性化合物，对人和动物的恶性肿瘤具有高效性。最常用的亚硝脲类药物，洛莫司汀和卡莫司汀，已知具有肝毒性，可诱发胆管周围炎和肝内胆汁淤积，长期来看会导致胆小管溶解和胆汁性肝硬化。然而，已证明亚硝脲类药物福莫司汀在20毫克/千克和50毫克/千克剂量时无肝毒性。我们研究了这三种亚硝脲对大鼠肝细胞的细胞毒性和细胞动力学的影响。洛莫司汀和卡莫司汀在体内改变肝细胞的增殖指数：流式细胞荧光术显示，洛莫司汀和卡莫司汀的DNA细胞分布相当相似，随后细胞在G2 + M期积累。3个月后，较低剂量的洛莫司汀和卡莫司汀出现退行性形态学和细胞周期紊乱。洛莫司汀（50毫克/千克）出现的病变最为严重。福莫司汀无肝毒性，优先诱发S期紊乱。毒性更强的亚硝脲类药物，洛莫司汀和卡莫司汀，诱发的肝细胞细胞周期改变相当，与肝毒性较小的亚硝脲类药物福莫司汀诱发的改变不同。
