Enhancement of 5-Fluorouracil Chemotherapeutic Efficacy

增强5-氟尿嘧啶化疗效果

• 批准号: 6550790
• 负责人: Mahmoud H el Kouni
• 金额: $ 17.69万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6550790
• 关键词: chemical synthesis; dosage; drug design /synthesis /production; drug interactions; drug screening /evaluation; enzyme inhibitors; fluorouracil; laboratory mouse; oral administration; thiouracil; uridine; uridine phosphorylase

DESCRIPTION (provided by applicant): 5-Fluorouracil (FUra) is among the few "standard" drugs effective against solid tumors in man (e.g. colorectal, breast, and head and neck cancers). FUra is the only drug in the market that shows synergism with most other anti-cancer agents in combination therapy. However, the full chemotherapeutic potential of FUra has not yet been totally realized. Increasing the dose of FUra to improve its efficacy has been hampered by host-toxicity. Uridine has been shown to allow increasing FUra doses which resulted in better anticancer efficacy and without the host-toxicity associated with high doses of FUra. Nevertheless, because of its rapid degradation, large doses (10-12 g/m2) of uridine are required in such regimens, and such doses induce toxic side-effects. We have designed and synthesized PTAU (5-phenylthioacyclouridine) as a potent and specific inhibitor of uridine degradation. Our preliminary results indicate that PTAU is not toxic and is 100% orally bioavailable. Furthermore, oral PTAU significantly increased the bioavailable uridine to adequate levels for a period of time sufficient to protect from the toxicity of high doses of FUra required for better anticancer activity. The overall objective of this proposal is to expand our preliminary results and explore the feasibility of modulating and increasing the concentration and half life of plasma uridine by PTAU and (2) to determine the effects of this compound on the chemotherapeutic efficacy and host-toxicity of FUra in mice. The goal is to improve the therapeutic index of this important anticancer drug through enhancing its efficacy by administering higher doses, while preventing the host-toxicity associated with such high doses. Two patents [(US Patents 5,476,855 (1995) and 5,721,241 (l998)] have been awarded to protect the technology and were licensed to the Company. Because of the importance and large market for Fura chemotherapy, the clinical and financial impact of the technology are quite substantial. Should PTAU prove to be effective in these Phase 1 studies, we will propose in Phase 2 to perform the pharmacokinetic, efficacy and toxicology studies needed for an IND filing with FDA . PROPOSED COMMERCIAL APPLICATION: The commercial potential for the proposed combination therapy is considerable. The sales of FUra represents a substantial market. Currently FUra is one of the principal drugs used in the clinic for the treatment of solid cancers. However, its full chemotherapeutic potential has not yet been fully realized because of the toxic limitations of higher doses. The proposed technology is aimed at increasing the doses of FUra for better anticancer efficacy without causing host toxicity. This will increase the use of FUra and enhance its commercial potential. Two patents have been awarded to protect the technology and were licensed to the Company.

描述（由申请人提供）：5-氟尿嘧啶（Fura）是对男子实体瘤有效的少数“标准”药物之一（例如结直肠，乳房和头颈癌）。 FURA是市场上唯一显示与大多数其他抗癌药联合治疗中的协同作用的药物。但是，Fura的全部化学治疗潜力尚未完全实现。宿主毒性增加了Fura剂量以提高其疗效的剂量。尿苷已显示可允许增加fura剂量，从而提高抗癌功效，并且没有与高剂量的Fura相关的宿主毒性。然而，由于其快速降解，在这种方案中需要大剂量（10-12 g/m2）的尿苷，并且这种剂量会诱导有毒的副作用。我们已经设计和合成了PTAU（5-苯基硫代酰胺）作为尿苷降解的有效和特异性抑制剂。我们的初步结果表明，PTAU无毒，100％口服生物利用。此外，口服PTAU在一段时间内显着将生物利用的尿苷显着提高到足够的水平，以免为更好的抗癌活性提供高剂量的Fura毒性。该提案的总体目的是扩大我们的初步结果，并探索PTAU和（2）调节和增加血浆尿苷的浓度和半寿命的可行性，以确定该化合物对小鼠FURA的化学治疗效率和宿主毒性的影响。目的是通过施用更高剂量来提高其功效，同时防止与如此高剂量相关的宿主毒性，从而提高其疗效，以提高这种重要的抗癌药物的治疗指数。两项专利[（美国专利5,476,855（1995）和5,721,241（L998）]已被授予保护该技术并获得公司的许可。由于Fura化学疗法的重要性和大型市场，对技术的临床和财务影响的临床和财务影响很大，应该在这些阶段中进行阶段。向FDA提交IND所需的功效和毒理学研究。 拟议的商业应用：拟议组合疗法的商业潜力相当大。 Fura的销售代表了一个实质性的市场。目前，Fura是诊所中用于治疗固体癌症的主要药物之一。 但是，由于较高剂量的毒性限制，其全部化学治疗潜力尚未完全实现。 提出的技术旨在增加Fura剂量，以提高抗癌功效，而不会引起宿主毒性。 这将增加Fura的使用并增强其商业潜力。 已授予了两项专利保护技术并获得了公司许可。

项目成果

Modulation of 5-fluorouracil host-toxicity and chemotherapeutic efficacy against human colon tumors by 5-(Phenylthio)acyclouridine, a uridine phosphorylase inhibitor.

通过 5-(苯硫基)无环尿苷（一种尿苷磷酸化酶抑制剂）调节 5-氟尿嘧啶宿主毒性和对人结肠肿瘤的化疗功效。

• DOI: 10.1007/s00280-006-0213-x
• 发表时间: 2006
• 期刊: Cancer chemotherapy and pharmacology.
• 作者: AlSafarjalani,OmarN;Rais,Reem;Shi,Junxing;Schinazi,RaymondF;Naguib,FardosNM;elKouni,MahmoudH
• 通讯作者: elKouni,MahmoudH