Novel Small-molecule TNF-a Modulators as Chemoprotective Agents

作为化学保护剂的新型小分子 TNF-a 调节剂

• 批准号: 7744464
• 负责人: Jiajiu Shaw
• 金额: $ 15.49万
• 依托单位: 21ST CENTURY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744464
• 关键词: Acids; Acute; Adverse effects; Affect; Alanine Transaminase; Amifostine; Animals; Aspartate Transaminase; Biological; Biological Availability; Carboplatin; Chemoprotection; Chemoprotective Agent; Cisplatin; Clinical; Cytotoxic agent; Development; Dosage Forms; Dose; Drug Kinetics; FDA approved; Foundations; Goals; Grant; Half-Life; Hepatotoxicity; Hypotension; Infusion procedures; Injection of therapeutic agent; Licensing; Liver; Malignant Neoplasms; Mus; Myelosuppression; Nausea and Vomiting; Oral; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platinum; Production; Protective Agents; Radiation; Radiation therapy; Radioprotection; Reducing Agents; Research; Research Contracts; Small Business Innovation Research Grant; Solid; Sulfur; TNF gene; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Protocols; Tumor Necrosis Factor-alpha; Up-Regulation; Work; cancer cell; cell killing; chemotherapy; improved; in vivo; killings; nephrotoxicity; novel; oxaliplatin; pre-clinical; preclinical study; prevent; public health relevance; small molecule; tumor

DESCRIPTION (provided by applicant): Cisplatin is a widely used cytotoxic agent with therapeutic activity against various tumors, but also with substantial side effects, including nephrotoxicity, hepatotoxicity and myelosuppression. Therefore, a chemoprotective agent which reduces the side effects of cisplatin without affecting it efficacy would have significant clinical benefit. Currently, amifostine is the only FDA approved chemoprotective drug for cisplatin therapy. Amifostine is a sulfur-containing agent that reduces side effects resulted from both chemotherapy (including cisplatin) and radiotherapy regimens. Unfortunately, there are significant limitations associated with amifostine including (1) both amifostine and its active metabolite have very short half-lives in vivo requiring amifostine to be administered by a 15 minute infusion 30 minutes before cisplatin injection, and (2) amifostine is associated with side-effects including nausea and vomiting, as well as transient hypotension. Therefore, amifostine is not an ideal chemoprotector. An ideal chemoprotector should be orally administratable, with a longer half-life as compared to amifostine, and with little or no toxicity by itself. As such, we are proposing to investigate several novel small-molecule modulators of tumor necrosis factor alpha (TNF?), specifically UTL-5b, -5d, and -5g, as improved chemoprotective agents. UTL-5g will be the leading candidate for this Phase I study due to its promising biological effects and extremely low acute toxicity while UTL-5b and -5d will be backup compounds. UTL-5g is the subject compound in our recently completed SBIR Phase I grant for liver radioprotection (# 1 R43 CA117033-01A1). As a result, we have obtained promising results which are supportive of this proposal. The specific aims of this Phase I study are: (1) to conduct an animal study to show the chemoprotective effect of UTL-5g for cisplatin-induced side effects; the dose of UTL-5g with maximal protection will also be determined, (2) to conduct an animal study to show that UTL-5g does not decrease cancer killing during cisplatin therapy, and (3) to conduct a pharmacokinetic study to determine the half life of UTL-5g, and any metabolite(s). Once this phase I study is completed, we will know (1) whether UTL-5g reduces nephrotoxicity, hepatotoxicity, and/or myelosuppression induced by cisplatin in mice, (2) the optimal dose of UTL-5g for chemoprotection against cisplatin treatment in mice, (3) whether UTL-5g compromises cisplatin's anti-tumor activity in mice, and (4) the half-life of UTL-5g in mice and any metabolite(s). PUBLIC HEALTH RELEVANCE: This phase I study will focus on the feasibility of using a small-molecule TNF- modulator, UTL-5g, as a chemoprotector to prevent/reduce side effects induced by cisplatin.

描述（由申请人提供）：顺铂是一种广泛使用的细胞毒性药物，对各种肿瘤具有治疗活性，但也具有显著的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，减少顺铂的副作用而不影响其功效的化学保护剂将具有显著的临床益处。目前，amifostine是FDA批准的唯一用于顺铂治疗的化学保护药物。氨磷汀是一种含硫药物，可减少化疗（包括顺铂）和放疗方案引起的副作用。不幸的是，存在与氨磷汀相关的显著限制，包括（1）氨磷汀及其活性代谢物在体内具有非常短的半衰期，需要在顺铂注射前30分钟通过15分钟输注给予氨磷汀，和（2）氨磷汀与包括恶心和呕吐以及短暂性低血压的副作用相关。因此，氨磷汀不是一种理想的化学保护剂。理想的化学保护剂应该是口服给药的，与氨磷汀相比具有更长的半衰期，并且本身具有很少或没有毒性。因此，我们建议研究几种新的肿瘤坏死因子α（TNF？）小分子调节剂，特别是UTL-5 b、-5d和-5g作为改进的化学保护剂。UTL-5g由于其有前途的生物学效应和极低的急性毒性，将成为这项I期研究的主要候选化合物，而UTL-5 b和-5d将作为备用化合物。UTL-5g是我们最近完成的SBIR I期肝脏放射保护资助中的受试化合物（# 1 R43 CA 117033 - 01 A1）。因此，我们已经获得了有希望的结果，这是支持这一建议。该I期研究的具体目的是：（1）进行动物研究以显示UTL-5g对顺铂诱导的副作用的化学保护作用;还将确定具有最大保护作用的UTL-5g的剂量，（2）进行动物研究以显示UTL-5g在顺铂治疗期间不降低癌症杀伤，和（3）进行药代动力学研究以确定UTL-5g和任何代谢物的半衰期。一旦该I期研究完成，我们将知道（1）UTL-5g是否减少小鼠中由顺铂诱导的肾毒性、肝毒性和/或骨髓抑制，（2）UTL-5g用于小鼠中针对顺铂治疗的化学保护的最佳剂量，（3）UTL-5g是否损害顺铂在小鼠中的抗肿瘤活性，以及（4）UTL-5g在小鼠和任何代谢物中的半衰期。公共卫生相关性：该I期研究将重点关注使用小分子TNF调节剂UTL-5g作为化学保护剂以预防/减少顺铂诱导的副作用的可行性。

项目成果

Using a simple HPLC approach to identify the enzymatic products of UTL-5g, a small molecule TNF-α inhibitor, from porcine esterase and from rabbit esterase.

使用简单的 HPLC 方法从猪酯酶和兔酯酶中鉴定 UTL-5g（一种小分子 TNF-α 抑制剂）的酶产物。

• DOI: 10.1016/j.jchromb.2013.09.021
• 发表时间: 2013
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Swartz,Kenneth;Zhang,Yiguan;Valeriote,Frederick;Chen,Ben;Shaw,Jiajiu
• 通讯作者: Shaw,Jiajiu

The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo.

小分子TNF-α调节剂UTL-5g可减少顺铂引起的副作用，增强顺铂在体内的治疗效果。

• 发表时间: 2011
• 期刊: Journal of experimental therapeutics & oncology
• 作者: Shaw,JiaJiu;Chen,Ben;Huang,Wen-Hsin;Lee,An-Rong;Media,Joseph;Valeriote,FrederickA
• 通讯作者: Valeriote,FrederickA