Novel Small-molecule TNF-a Modulators as Chemoprotective Agents

描述(申请人提供)：顺铂是一种广泛使用的细胞毒剂，对各种肿瘤具有治疗活性，但也有很大的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，一种在不影响顺铂疗效的情况下减少顺铂副作用的化学保护剂将具有显著的临床益处。目前，氨磷汀是FDA批准的唯一用于顺铂治疗的化学保护性药物。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，氨磷汀有很大的局限性，包括(1)氨磷汀及其活性代谢物在体内的半衰期都很短，需要在顺铂注射前30分钟输注15分钟，以及(2)氨磷汀与包括恶心和呕吐在内的副作用以及一过性低血压有关。因此，氨磷汀不是理想的化学保护剂。理想的化学保护剂应该是口服的，与氨磷汀相比半衰期更长，本身毒性很小或没有。因此，我们建议研究几种新的肿瘤坏死因子α小分子调节剂，特别是UTL-5b、-5d和-5g，作为改进的化学保护剂。UTL-5g因其良好的生物学效应和极低的急性毒性，将是这项第一阶段研究的首选候选药物，而UTL-5b和-5d将作为备用化合物。UTL-5G是我们最近完成的SBIR肝脏放射防护第一阶段授权的主题化合物(#1 R43 CA117033-01A1)。因此，我们取得了支持这一提议的有希望的结果。这项第一阶段研究的具体目的是：(1)进行动物实验，以展示UTL-5G对顺铂所致副作用的化疗保护作用，并确定具有最大保护作用的UTL-5G的剂量；(2)进行动物实验，证明UTL-5G在顺铂治疗过程中对肿瘤的杀伤作用；(3)进行药代动力学研究，以确定UTL-5G及其代谢物(S)的半衰期。一旦这项I期研究完成，我们将了解(1)UTL-5G是否可以减少顺铂引起的小鼠肾毒性、肝毒性和/或骨髓抑制；(2)UTL-5G对抗顺铂治疗的最佳化疗剂量；(3)UTL-5G是否降低了顺铂在小鼠体内的抗肿瘤活性；以及(4)UTL-5G在小鼠和任何代谢物(S)中的半衰期。公共卫生相关性：这项第一阶段的研究将集中在使用小分子肿瘤坏死因子调节剂UTL-5G作为化疗保护剂以预防/减少顺铂引起的副作用的可行性。

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.