Design and development of anti-tumor drugs using the energy metabolism specifically held in tumor cells as potential targets

各种化学物质已被确定为抗癌药物的潜在候选物。然而，由于它们对肿瘤细胞的选择性毒性较低，大多数具有较强的副作用。为了克服这个问题，必须建立对肿瘤细胞具有高度选择性毒性的化学物质。为了探索理想的候选抗肿瘤药物，在本研究中，我们试图表征肿瘤细胞特异性持有的能量代谢。结果表明：1.实验结果表明：我们发现II型己糖激酶的转录水平在恶性肿瘤细胞中是显著的。定量分析显示其在肿瘤细胞中的表达水平高达2.5 fmol/mg poly(A)^+ rna。我们接下来探讨在什么条件下II型己糖激酶的表达变得显著。结果，在大鼠腹腔培养AH130细胞时，II型己糖激酶的转录水平是显著的。然而，当该细胞系在培养皿中生长时，II型己糖激酶的转录水平明显低于腹水细胞。这些结果表明，II型己糖激酶的转录水平可能随培养条件的变化而变化。为了了解这种显著的变化是如何引起的，我们研究了缺氧和血清刺激的可能参与。结果，II型己糖激酶基因表达在血清刺激下显著升高。基于这些结果，我们认为肿瘤细胞的糖代谢途径会随着生长条件的改变而改变，这种改变主要是由血清反应因子介导的。这些发现对新的抗肿瘤药物的设计和开发具有重要的指导意义。我们现在正在探索能够特异性抑制肿瘤细胞生长的候选化合物。

Various chemicals have been established as potential candidates of anticancer drugs. However, due to their low selective toxicity against tumor cells, most of them show strong side effects. To overcome this problem, chemicals showing highly selective toxicity against tumor cells must be established. To explore desirable candidates of anti-tumor drugs, in this study, we tried to characterize the energy metabolism specifically held in tumor cells. As a result, following results were obtained.1. We found that the transcript level of type II hexokinase was remarkable in malignant tumor cells. Quantitative analysis showed that the level of its expression in tumor cells were as high as 2.5 fmol/mg poly(A)^+ RNA.2. We next explored under which condition the expression of type II hexokinase become remarkable. As a result, transcript level of type II hexokinase was remarkable when AH130 cells were grown in an abdominal cavity of rats. However, when this cell line was grown in culture dishes, the transcript level of type II hexokinase was remarkably lower than that observed with ascites cells. These results indicate that the transcript level of type II hexokinase could be changes accompanied by changes in culture conditions.3. To understand how such remarkable change is caused, we examined possible involvement of hypoxia and serum stimulation. As a result, gene expression of type II hexokinase was remarkably elevated by serum stimulation.Based on these results, we concluded that the metabolic pathway of sugar in tumor cells could be changed accompanied by changes in their growth conditions and that this change is mainly mediated by serum responsive factor. These findings are very helpful for design and development of new anti-tumor drugs. We are now exploring candidate compounds which specifically suppress the growth of tumor cells.