Novel Small-molecule TNF-a Modulators as Chemoprotective Agents

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.