Selective modification of sterol composition of hepatomas: new opportunities for chemotherapy
Selective modification of sterol composition of hepatomas: new opportunities for chemotherapy
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DOI：
10.1054/mehy.1995.0678
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发表时间：
1999-05-01
影响因子：
4.7
通讯作者：
Feigin, AM
中科院分区：
文献类型：
--
作者：
Feigin, AM
肝癌中胆固醇生物合成的反馈调节的缺乏提示了胆固醇被其生物合成前体替代的可能性（7-脱氢胆固醇或羊毛甾醇）选择性地在肝癌中，而这些前体在肝脏和其他正常组织中没有积累，通过高胆固醇饮食和胆固醇生物合成的特异性抑制剂的组合（AY-9944用于7-脱氢胆固醇蓄积，酮康唑用于羊毛甾醇蓄积）。我们建议：（1）利用7-脱氢胆固醇在肝癌细胞质膜上的选择性积累来增加肝癌细胞对多烯抗生素的敏感性（抗生素B，制霉菌素），因为多烯抗生素与胆固醇相比对7-脱氢胆固醇具有更高的亲和力;（2）利用羊毛甾醇在肝癌细胞中的选择性积累来增加肝癌细胞对不同抗肿瘤剂的敏感性，因为与胆固醇相比，羊毛甾醇在支持重要细胞功能（包括天然膜的屏障性质）方面的有效性低得多。
The absence of feedback regulation of cholesterol biosynthesis in hepatomas suggests the possibility of substitution of cholesterol with its biosynthetic precursors (7-dehydrocholesterol or lanosterol) selectively in hepatomas without the accumulation of these precursors in liver and other normal tissues, by a combination of a high cholesterol diet and specific inhibitors of cholesterol biosynthesis (AY-9944 for accumulation of 7-dehydrocholesterol and ketoconazole for accumulation of lanosterol). We suggest: (1) using a selective accumulation of 7-dehydrocholesterol in hepatoma plasma membranes to increase the sensitivity of hepatoma cells to polyene antibiotics (amphotericin B, nystatin), because polyene antibiotics have higher affinity to 7-dehydrocholesterol compared to cholesterol; (2) using a selective accumulation of lanosterol in hepatoma cells to increase the sensitivity of hepatoma cells to different antitumor agents, because lanosterol is much less effective in supporting vital cell functions (including barrier properties of natural membranes) compared to cholesterol.