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

基于新作用机制的抗癌药物开发研究

基本信息

批准号：
10672065
负责人：
TAKAHASHI Noriko
金额：
$ 1.6万
依托单位：
Hoshi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672065/
关键词：
Retinoic acid Retinoylation Retinoyl-CoA synthetase Differentiation Retinoyl-CoA Retinoyl-CoA transferase Cancer Rat tissues

项目摘要

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.

视黄酸（RA）在临床上用于治疗增生的皮肤病和白血病，以及预防某些肿瘤。然而，仅RA在几个月内复发，急性前临床白血病患者的急性临床细胞性白血病患者比例很高。大多数复发患者对RA的进一步治疗具有抗性。这使我们通过阐明视网膜化（通过蛋白质酰化）来开发新药物，W3HCH RA的一种新的非基因组机制可能作用于细胞。我们发现最近确定了新的立体定向和波利恩增强的RA作用，细胞分化的诱导以及增加了视网膜化的程度。此外，它们是唯一的代理人，暴露了抗癌活动。视网膜化的一种代谢途径是形成视网膜中间的视网膜中间体，随后转移和共价结合与蛋白质。我们通过使用大鼠组织建立了视网膜化，视网膜-COA合成酶和视网膜-COA转移的体外测定法。酶活性取决于时间，以及可饱和方式的底物和酶的浓度。 ATP，COA和MHCLI D22的任何遗漏导致视网膜-COA形成显着降低。视网膜化水平与在大鼠肝脏，睾丸和肾脏的粗提取物中形成的视网膜-COA的量成正比，并且它们之间存在正相关。这些结果表明，在大鼠肝脏中存在RA的ATP依赖性视网膜-COA形成的酶活性。两种外部活性的既定灵敏方法似乎都可以澄清视网膜的身体作用。正在进行研究，以确定RA和多烯对动物肿瘤的毒性和有效性。