盐酸米托蒽醌脂质体的药效学及毒性研究

目的对盐酸米托蒽醌脂质体(Mit-lipo)与盐酸米托蒽醌普通制剂(Mit-inj)进行药效学及毒性比较研究。方法采用小鼠肝癌H22、小鼠前列腺癌RM-1移植肿瘤模型探讨Mit-lipo的抗肿瘤作用;犬急性毒性、大鼠和犬长期毒性研究比较Mit-lipo和Mit-inj毒性差异。结果 Mit-lipo 1、2、4和6 mg.kg-1各剂量对H22实体瘤的抑瘤率分别为75.1%、76.5%、90.1%和93.8%,也可剂量依赖性抑制小鼠前列腺癌RM-1肿瘤的生长,与等剂量的Mit-inj相比疗效明显增强。犬急性毒性结果表明Mit-lipo最大耐受剂量(MTD)为2.0 mg.kg-1,毒性表现为轻微至中度的皮肤毒性,给药4周后皮肤毒性逐渐减轻。大鼠长期毒性结果表明Mit-lipo可明显降低Mit-inj引起的骨髓毒性,并产生新的皮肤毒性反应。犬长期毒性结果表明Mit-lipo 0.1、0.3和0.45mg.kg-1组主要毒性反应为轻微至轻度的皮肤毒性反应,主要毒性靶器官为睾丸和皮肤,MTD为0.45 mg.kg-1,Mit-inj0.45 mg.kg-1可致WBC和PLT值降低和睾丸毒性病变。结论与普通制剂相比,米托蒽醌脂质体的体内抑瘤效果明显增强,且骨髓毒性明显降低。

Pharmacodynamics and toxicity of liposomal mitoxantrone hydrochloride

Aim To compare the pharmacodynamics and toxicity of liposomal mitoxantrone(Mit-lipo) and free mitoxantrone(Mit-inj).Methods The antineoplastic effect of Mit-lipo was evaluated in H22 and RM-1 mice xenograft tumor model.The toxic differences between Mit-lipo and Mit-inj were performed through acute toxicity of dogs and long-term toxicity of rats and dogs.Result The tumor-inhibition rates of Mit-lipo(1,2,4 and 6 mg·kg-1) in H22 bearing mice were 75.1%,76.5%,90.1% and 93.8% respectively,and the same doses also inhibited RM-1 tumor growth in a dose-dependent manner.The antitumor effect studies showed that Mit-lipo significantly improved the therapeutic effect in comparison with free drug.The results of acute toxicity of dogs showed that maximum tolerated dose of Mit-lipo was 2.0 mg·kg-1 with the dermal toxicity from mild to moderate,and the toxicity resumed slowly after dosing four weeks.In long-term toxicity of rats,the bone marrow and dermal toxicity were observed in Mit-lipo,and the suppression of bone marrow was reduced significantly compared with Mit-inj.In the long-term toxicity of dogs study,mild dermal toxicity was observed at the dose of 0.1,0.3 and 0.45 mg·kg-1 of Mit-lipo,and the target organs were testis and skin.The maximum tolerated dose of Mit-lipo was 0.45 mg·kg-1,and Mit-inj(0.45 mg·kg-1) resulted in the reduce of WBC and PLT and the lesions of testis.Conclusion Compared with Mit-inj,Mit-lipo can increase therapeutic effect and improve toxicity of the bone marrow obviously.