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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.

维甲酸(RA)在临床上用于治疗增生性皮肤病和白血病，并用于预防某些肿瘤。然而，由RA单独诱导的完全缓解的急性早幼粒细胞白血病患者中，有很高比例的患者在几个月内复发。大多数复发患者对RA的进一步治疗具有抵抗力。这使得我们可以通过阐明视黄酸(RA对蛋白质的酰化)来开发新药，这是RA可能作用于细胞的一种新的非基因组机制。我们发现，最近发现的新类固醇和多烯增强了RA的作用，诱导了细胞分化，并增加了视黄酸甲基化的程度。此外，他们作为独家代理，展示了抗癌活性。视黄酰化的一个代谢途径是形成视黄酰辅酶A中间体，随后维甲酸部分转移和共价结合到蛋白质上。我们建立了大鼠组织中视黄酰化、视黄酰辅酶A合成酶和视黄酰辅酶A转移酶的体外检测方法。酶的活性依赖于时间，底物和酶的浓度呈饱和关系。去掉三磷酸腺苷、辅酶A和MhC lィイD22ィエD2中的任何一个，维甲酰辅酶A的生成都显著减少。大鼠肝脏、睾丸和肾脏粗提物中视黄酰辅酶A的生成量与视黄酸化程度成正比，且呈正相关。这些结果表明，在大鼠肝脏中存在一种酶活性，它负责维甲酸形成依赖于ATP的视黄酰辅酶A。建立的这两种酶活性的灵敏方法对于阐明视黄酸的生理作用似乎是有用的。目前正在进行研究，以确定RA和多烯类化合物联合治疗动物肿瘤的毒性和有效性。