Analog Studies of 4-HPR and its Glucuronide

4-HPR及其葡萄糖苷酸的类似物研究

基本信息

批准号：
8231448
负责人：
Robert W Curley
金额：
$ 33.17万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231448
关键词：
4-hydroxybenzylretinone Amides Apoptosis Apoptosis Promoter Back Binding Biological Breast Cancer Model Cancer Patient Cell Culture Techniques Cells Chemoprevention Chemopreventive Agent Chemotherapy-Oncologic Procedure Chronic Clinical Dermatologic Agents Development Dose Evaluation Event Fenretinide Glucosides Glucuronides Glycosides Health Hydrolysis Left Link MCF7 cell Malignant Neoplasms Mammary Neoplasms Modeling Molecular Morbidity - disease rate Mouse Mammary Tumor Virus Mus Nuclear Oxygen Parents Pregnancy Preparation Preventive Process Production Property Rattus Relative (related person)Research Research Personnel Retinoic Acid Receptor Retinoid Receptor Retinoids Risk Series Stress Structure Teratology Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Tretinoin Vitamin A analog base cancer chemoprevention chemotherapeutic agent chemotherapy design dimethylbenzanthracene fetal in vivo interest malformation malignant breast neoplasm mortality neoplastic cell prevent research study retinamide retinoyl glucuronide scale up sugar tool tumor

项目摘要

DESCRIPTION (provided by applicant): All-trans Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds share teratogenic potential and the tendency to cause vitamin A toxicities. However, the O-acyl glucuronide metabolite of RA has been suggested to be a less toxic, active material. The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) shows some unique activity as a breast cancer chemopreventive with further reduced toxicity and teratogenicity. Our own studies with 4-HPR-O-glucuronide (4-HPROG) have shown it to be an even less toxic, more effective preventive and therapeutic for DMBA-induced rat mammary tumors relative to 4-HPR. However, these glucuronides as well as the retinamide 4-HPR are unstable to hydrolysis back to the parent retinoid making it unclear what the active forms of the molecules are. We have been synthesizing stable C-linked analogs of 4- HPR and 4-HPROG for evaluation as breast cancer chemopreventive/chemotherapeutic agents. A number of these analogs show increased potency preventing DMBA-induced tumors and further reduced toxicity relative to 4-HPR. Like 4-HPR, these analogs bind weakly to the known nuclear retinoid receptors and, unlike RA, cause apoptosis in tumor cells in a manner that is not inhibited by retinoid receptor antagonists, leaving their mechanism of action incompletely understood. The specific aims of our proposed continued research are: 1) to scale up production of our preferred analog (4-HBR, 4-HBRCG, or 4-HBRCglucose) based on a current chemotherapy/chemoprevention experiment underway, 2) to complete chemoprevention evaluation of the chosen analog in the DMBA-induced rat mammary tumor model, 3) to begin study of the chosen analog in a second (MMTV/ErbB2 mouse) mammary tumor model, 4) to conduct predictive teratology studies of the chosen analog(s), and 5) to explore mechanism of action issues with the chosen analog(s) focusing on our observations that 4-HPR and our analogs appear to induce ER stress. We will focus here on establishing the necessity of these phenomena for the actions of these compounds as well as determining molecular players upstream of these processes which trigger these events. PUBLIC HEALTH RELEVANCE: Despite recent advances, breast cancer-associated morbidity and mortality remains a serious problem in the USA. The analogs of 4-HPR we are developing, show real promise as more effective and less toxic preventive and therapeutic agents for breast cancer. A clearer understanding of how these promising molecules function would further enhance our ability to develop and exploit them.

描述（由申请人提供）：全反式视黄酸（RA）及其类似物已作为皮肤病药物和潜在的癌症化学预防/化疗药物出现。作为一类化合物，这些化合物具有致畸潜力和引起维生素 A 毒性的倾向。然而，RA 的 O-酰基葡萄糖醛酸代谢物被认为是一种毒性较小的活性物质。合成类视黄醇 N-(4-羟基苯基) 视黄酰胺 (4-HPR) 作为乳腺癌化学预防剂显示出一些独特的活性，并进一步降低了毒性和致畸性。我们自己对 4-HPR-O-葡萄糖醛酸苷 (4-HPROG) 的研究表明，相对于 4-HPR，它对于 DMBA 诱导的大鼠乳腺肿瘤的毒性更低、更有效的预防和治疗作用。然而，这些葡萄糖醛酸苷以及视黄酰胺 4-HPR 不稳定，不能水解回母体视黄醇，因此尚不清楚这些分子的活性形式是什么。我们一直在合成 4-HPR 和 4-HPROG 的稳定 C 连接类似物，用于评估其作为乳腺癌化学预防/化疗药物的效果。相对于 4-HPR，这些类似物中的许多类似物显示出增强的预防 DMBA 诱导的肿瘤的效力，并进一步降低了毒性。与 4-HPR 一样，这些类似物与已知的核视黄酸受体结合较弱，并且与 RA 不同，它们以不受视黄酸受体拮抗剂抑制的方式引起肿瘤细胞凋亡，因此其作用机制尚未完全了解。我们提议的持续研究的具体目标是：1) 基于当前正在进行的化疗/化学预防实验，扩大我们首选类似物（4-HBR、4-HBRCG 或 4-HBRC 葡萄糖）的生产，2) 完成化学预防评估在 DMBA 诱导的大鼠乳腺肿瘤模型中选择类似物，3) 开始在第二个（MMTV/ErbB2 小鼠）乳腺肿瘤模型中研究所选类似物， 4) 对所选类似物进行预测性畸形学研究，5) 探索所选类似物的作用机制，重点关注我们观察到的 4-HPR 和我们的类似物似乎会诱导 ER 应激。我们将在这里重点关注确定这些现象对于这些化合物的作用的必要性，以及确定触发这些事件的这些过程上游的分子参与者。公共卫生相关性：尽管最近取得了进展，但乳腺癌相关的发病率和死亡率在美国仍然是一个严重的问题。我们正在开发的 4-HPR 类似物显示出作为更有效、毒性更低的乳腺癌预防和治疗剂的真正前景。更清楚地了解这些有前途的分子如何发挥作用将进一步增强我们开发和利用它们的能力。