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

各种化学品已被确定为抗癌药物的潜在候选者。然而，由于它们对肿瘤细胞的低选择性毒性，它们中的大多数显示出强烈的副作用。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品。为了探索抗肿瘤药物的理想候选者，在本研究中，我们试图表征肿瘤细胞中特定的能量代谢。结果表明：1.我们发现在恶性肿瘤细胞中II型己糖激酶的转录水平是显著的。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.我们接下来探索在何种条件下II型己糖激酶的表达变得显著。结果，当AH 130细胞在大鼠腹腔中生长时，II型己糖激酶的转录水平显著。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显著低于用腹水细胞观察到的水平。这些结果表明，随着培养条件的改变，II型己糖激酶的转录水平也会发生变化.为了了解这种显着的变化是如何引起的，我们检查了可能涉及缺氧和血清刺激。结果表明，血清刺激可显著提高II型己糖激酶的基因表达，提示肿瘤细胞生长条件的改变可导致糖代谢途径的改变，而这种改变主要由血清反应因子介导。这些发现对于设计和开发新的抗肿瘤药物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.