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潜在的抗癌药物候选药物。然而，由于它们对肿瘤细胞的选择性毒性较低，大多数药物都表现出较强的副作用。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。为了探索理想的抗肿瘤药物候选药物，在这项研究中，我们试图表征肿瘤细胞中特有的能量代谢。结果，取得了以下成果：1.我们发现，在恶性肿瘤细胞中，II型己糖激酶的转录水平非常显著。定量分析显示其在肿瘤细胞中的表达水平高达2.5fmol/mg聚(A)？RNA2。接下来，我们探索了在什么条件下，II型己糖激酶的表达变得显著。结果表明，AH130细胞在大鼠腹腔内生长时，II型己糖激酶的转录水平显著升高。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在腹水细胞中观察到的水平。这些结果表明，II型己糖激酶的转录水平可能会随着培养条件的改变而发生变化。为了了解这种显著的变化是如何引起的，我们研究了低氧和血清刺激的可能参与。根据这些结果，肿瘤细胞中糖的代谢途径可以随着生长条件的改变而改变，这种变化主要是由血清反应因子介导的。这些发现对抗肿瘤新药的设计和开发有很大的帮助。我们现在正在探索专门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.