TNF-alpha modulator as a radioprotector in liver

TNF-α 调节剂作为肝脏的放射保护剂

• 批准号: 7108260
• 负责人: Jiajiu Shaw
• 金额: $ 13万
• 依托单位: UNITECH PHARMACEUTICALS, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-10 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108260
• 关键词: liver; small molecule; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Cancer patients treated by radiation usually suffer organ damages in addition to other side effects (hair loss, nausea, and diarrhea). For example, patients with liver cancer, when treated by X-ray, suffer from liver damages and liver function reduction. Unfortunately, there is only one approved drug, Amifostine, to reduce head & neck damages caused by radiation, but not for liver damage. The direct effect of radiation therapy is to cause DNA damages (whether it be cancer cells or normal cells). In addition to the direct effect, there are also some indirect effects which can also cause liver damages. For example, the elevation of TNF-alpha levels in liver by radiation is an indirectly effect of radiation treatment; high levels of TNF-alpha appeared to cause liver damages. The applicant organization has a series of patented small-molecules TNF-alpha modulators. Out of these compounds, UTL-5b, -5d and -5g have been selected due to (a) their ability to modulate TNF-alpha and (b) they are associated with very high LD50 values and satisfactory results on a 14-day repeat dose toxicity study in mice. Preliminary study showed that when an animal was pre-treated with a small molecule TNF-alpha modulator (UTL-5d) before an X-ray treatment, liver damages appeared to be reduced. This preliminary study indicates that (1) TNF-alpha plays an important role in damaging the liver, and (2) a UTL-compound lowered TNF-alpha levels and may be a potential radiation protector for liver. The goal of this SBIR Phase I study is to validate the feasibility of using our TNF-alpha modulators to reduce liver damages on mice treated by radiation. Upon the approval of this Phase I study, the following specific aims of this Phase I study will be conducted: (1) Develop at least two injectable formulations employing these compounds; (2) Develop and validate an HPLC method for each of these formulations; (3) Conduct animal studies to confirm the radiation protection effects of UTL compounds; (4) Analyze TNF-alpha levels and attempt to correlate the reduction of TNF-alpha levels reduction with liver damages; (5) Conduct a radiation dose escalation study. The ultimate goal is to develop a radioprotective drug to be used in conjunction with radio therapy.

描述（由申请人提供）：接受放射治疗的癌症患者除了其他副作用（脱发、恶心和腹泻）外，通常还会遭受器官损伤。例如，患有肝癌的患者，当通过X射线治疗时，遭受肝脏损伤和肝功能降低。不幸的是，只有一种批准的药物阿米福汀可以减少辐射引起的头部和颈部损伤，但不能治疗肝脏损伤。放射治疗的直接效果是造成DNA损伤（无论是癌细胞还是正常细胞）。除了直接影响外，还有一些间接影响也会导致肝脏损伤。例如，通过辐射升高肝脏中的TNF-α水平是辐射治疗的间接效应;高水平的TNF-α似乎会导致肝脏损伤。申请组织拥有一系列获得专利的小分子TNF-α调节剂。在这些化合物中，选择UTL-5 B、-5d和-5g是因为（a）它们调节TNF-α的能力和（B）它们与非常高的LD 50值和令人满意的结果相关在小鼠中进行的14天重复给药毒性研究。初步研究表明，当动物在X射线治疗前用小分子TNF-α调节剂（UTL-5d）预处理时，肝损伤似乎减少。这项初步研究表明，（1）TNF-α在损害肝脏方面起着重要作用，（2）UTL化合物降低了TNF-α水平，可能是肝脏的潜在辐射保护剂。这项SBIR I期研究的目的是验证使用我们的TNF-α调节剂减少辐射治疗小鼠肝脏损伤的可行性。在本I期研究获得批准后，将进行本I期研究的以下具体目标：（1）开发至少两种使用这些化合物的注射制剂;（2）开发并验证每种制剂的HPLC方法;（3）进行动物研究以确认UTL化合物的辐射防护作用;（4）分析TNF-α水平并尝试将TNF-α水平的降低与肝损伤相关联;（5）进行辐射剂量递增研究。最终目标是开发一种与放射治疗结合使用的放射防护药物。