羟基喜树碱内酯环形式与其抗癌活性的关系

摘要

目的：研究10-羟基喜树碱(HCPT)的内酯环形式与抗癌活性之间的关系.方法：采用MTT和台盼蓝排染法测定两种内酯环形式的HCPT在体外对多种肿瘤细胞的作用，并在体内(0.5、1.0和2.0 mg/kg，ip)评价它们对S180肉瘤和HepS肝癌的抑瘤效果；应用HPLC方法观察了HCPT内酯环在肿瘤细胞内的转化情况.结果：两种形式的HCPT对同一种肿瘤细胞均显示类似的细胞毒性(P＞0.05)；但在体内实验中，闭环HCPT(C-HCPT)的抑瘤率明显高于(约两倍)开环HCPT(O-HCPT).采用HPLC方法分析证明，两种类型的HCPT能在一定条件(如pH改变等)下相互转化. 因此，O-HCPT体内、外作用的明显差异可归因于其在偏酸性环境(包括肿瘤细胞体外培养时)可较多地转化成C-HCPT，而在偏碱性环境(如正常体液pH约为7.40)中多呈开环形式.结论：闭环和开环HCPT羟基喜树碱均具有抗癌活性，但前者的活性较强；开环HCPT可在一定条件下转化成闭环形式.%AIM: To study the relationship between the lactone forms of 10-hydroxycamptothecin (HCPT) and their antitumor activities. METHODS: Antitumor activity of the two forms of HCPT was studied in vitro using seven cultured human and mouse tumor cell lines. Mice bearing sarcoma 180 and solid hepatoma were treated with HCPT (0.5, 1, and 2 mg/kg, ip) and tumor growth inhibition was assayed. HPLC method was employed to investigate the conversion of two forms of HCPT in different pH conditions and cultured tumor cells.RESULTS: It was found that both forms of HCPT (O-HCPT and C-HCPT) showed similar activities in vitro against a number of tumor cell lines at the same concentration; but C-HCPT was more effective (about two times ) than O-HCPT in vivo. The difference between in vitro and in vivo results could be explained by the conversion of O-HCPT into C-HCPT in a certain condition, which was shown by the HPLC analysis of HCPT at different pH values and in cultured tumor cells.rnCONCLUSION: Both forms of HCPT were effective against tumor growth, but C-HCPT was more effective than O-HCPT, the latter could be converted into the former under certain conditions.