Study for The Development of Anti-cancer Drug Based on A New Mechanism of Actions

视网膜酸（RA）是临床上用于促生长性皮肤病和白血病的治疗，也是在某些肿瘤的预防下使用的。However，一个高百分比的急性promyelocytic leukemiia患者在复合器中被诱导的RA独自在几个月内被释放。大多数与RA相关的患者都有抵抗力接受进一步治疗。这让我们用视网膜的提取（蛋白的氧化）来开发一种新的药物，W3 hich RA可能对细胞的一项新的非基因组机制。我们发现了最近发现的新类固醇和聚乙烯增强型RA反应，细胞分化的含义，并增加了视网膜的范围。在添加中，它们是一个单一的代理人，展示了抗癌症活动。retinoylation的一条代谢途径是retinoyl-CoA中间和亚序列转移和视网膜动力学与蛋白质的关联的形成。我们在体外分析中对视网膜、视网膜-CoA合成酶和视网膜-CoA转移酶进行了研究。Enzyme活性取决于时间，以及在一个可饱和的咒语中的基础和Enzyme的集中。ATP、CoA和MhCly D22和D2的发射在一个标记的还原中的retinoyl-CoA形成。retinoylation的水平很有可能是由于retinoyl-CoA的数量形成于大鼠liver、testis和kidney的crude提取物中，并且在它们之间存在着积极的相关性。这些结果表明，酶的活动是由ATP-依赖的视网膜-CoA形成的，对大鼠活体中的RA存在负责。The established sensitive method of both exzyme activities seems to be useful for the clarification of physiological role of the retinoylaton。Studies are presently underway to determine the toxicity and the effectiveness of combination of RA and polyenes on tumors growing in animals。

Retinoic acid (RA) is used clinically in the treatment of proliferative dermatological diseases and leukemia, and in the prevention of some tumors. However, a high percentage of acute promyelocytic leukemia patients in completer remission induced by RA alone relapsed within a few months. Most relapsed patients are resistant to further treatment with RA. This let us to develop new drugs by the elucidation of retinoylation (acylation by RA of protein), a new non-genomic mechanism by w3hich RA may act on cells. We found that recently identified new steroid and polyene enhanced RA action, the induction of cell differentiation, and increased the extent of retinoylation. In addition, they as a sole agent, exhibited anti-cancer activities. One metabolic pathway for retinoylation is the formation of a retinoyl-CoA intermediate and subsequent transfer and covalent binding of the retinoyl moiety to protein. We established in vitro assays for retinoylation, retinoyl-CoA synthetase and retinoyl-CoA transferase by using rat tissues. Enzyme activities depended on time, and the concentration of substrate and enzyme in a saturable manner. The omission of any of ATP, CoA and MhClィイD22ィエD2 resulted in a marked reduction of retinoyl-CoA formation. The level of retinoylation was proportional to the amount of retinoyl-CoA formed in crude extracts of rat liver, testis, and kidney, and there existed the positive correlation between them. These results indicate that the enzyme activity which is responsible for the ATP-dependent retinoyl-CoA formation from RA exists in rat liver. The established sensitive method of both exzyme activities seems to be useful for the clarification of physiological role of the retinoylaton. Studies are presently underway to determine the toxicity and the effectiveness of combination of RA and polyenes on tumors growing in animals.