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剂，重要的是寻找识别与正常细胞明显不同的肿瘤细胞的“特定状态”的化合物。能量转换膜系统，如线粒体，是研究这种可能性的良好模型，因为膜的状态根据它们的能量状态而变化。我们已经发现，环戊烯二酮类化合物是ATP合成所必需的无机磷酸盐转运的有效和特异性抑制剂。因此，我们使用了正常大鼠肝细胞和肿瘤细胞的线粒体，这两种细胞都产生ATP，以研究在各种条件下它们的膜上发生了什么变化，以及亲核性环戊烯二酮对它们的影响。我们分析了正常细胞和肿瘤细胞线粒体能量传递抑制剂的作用机制。结果表明：1）成功地从肿瘤细胞株AH130中制备了完整的线粒体。2）研制了一种新型的小尺寸TPP^+选择电极，该电极对TPP^+具有较高的灵敏度。使用该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换的环戊烯二酮类似物。3）此外，我们发现一些环戊烯二酮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.