Anti-tumor activity in relation to the effect on the energy transducting systems of the nucleophilic cyclopentendione derivatives.

为了开发新型抗肿瘤药物，寻找能够识别肿瘤细胞与正常细胞明显不同的“特定状态”的化合物是很重要的。像线粒体这样的能量传导膜系统是检验这种可能性的好模型，因为膜的状态会随着它们的能量状态而变化。我们已经发现，环戊二酮是ATP合成不可或缺的无机磷酸盐运输的有效和特异性抑制剂。因此，我们使用正常大鼠肝细胞和肿瘤细胞的线粒体来研究在不同条件下它们的膜发生了什么变化，以及亲核环戊二酮对它们的影响。我们分析了能量转导抑制剂对正常细胞和肿瘤细胞线粒体的作用机制和影响。结果如下：1)我们成功地从肿瘤细胞系ah132中制备了高度完整的线粒体。2)我们开发了一种新型的小尺寸的TPP^+选择性电极，该电极对TPP^+具有较高的灵敏度。利用这种电极分析线粒体的能量状态，我们成功地发现了几种抑制肿瘤细胞能量转导的环戊二酮类似物。3)此外，我们发现环戊二酮的一些类似物在肿瘤线粒体中比在正常线粒体中更有效地抑制磷酸转运蛋白。

For development of new types of anti-tumor agents, it is important to search for chemical compounds that recognize a "specific state" of tumor cells that is markedly different from that of normal cells. Energy transducing-membrane systems such as mitochondria are good models to use in examining this possibility, because the state of the membrane changes according to their energy state. We have already found that cyclopentendiones are potent and specific inhibitors of the transport of inorganic phosphate that is indispensable for ATP synthesis. Thus, we used mitochondria from normal rat liver cells, and tumor cells that both produce ATP to study what changes took place on their membranes under various conditions, and the effects of nucleophilic cyclopentendiones on them. We analyzed the mechanisms and the effects of the inhibitors of energy transduction on mitochondria from normal and tumor cells. The results were as follows.1)We succeeded in preparation of highly intact mitochondria from the tumor cell line AH130.2)We developed a new type of TPP^+-selective electrode of small size which showed high sensitivity for TPP^+. Using this electrode for analysis of the energy state of mitochondria, we succeeded in finding several analogs of cyclopentendiones that inhibited energy transduction in tumor cells.3)Furthermore, we found that some analogs of cyclopentendione inhibited phosphate transporter protein more efficiently in the tumor mitochondria than in normal mitochondria.