TNF-alpha modulator as a radioprotector in liver

描述(申请人提供)：接受放射治疗的癌症患者通常会遭受器官损伤，此外还会有其他副作用(脱发、恶心和腹泻)。例如，肝癌患者在接受X光治疗时，会出现肝脏损伤和肝功能下降。不幸的是，只有一种被批准的药物，氨磷汀，可以减少辐射引起的头颈部损伤，但不能治疗肝脏损伤。放射治疗的直接作用是造成DNA损伤(无论是癌细胞还是正常细胞)。除了直接的影响，还有一些间接的影响，也可以造成肝脏损害。例如，辐射导致肝脏中的肿瘤坏死因子-α水平升高是放射治疗的间接影响；高水平的肿瘤坏死因子-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肿瘤坏死因子-α调节剂。从这些化合物中选择UTL-5b、-5d和-5g是因为(A)它们有调节肿瘤坏死因子-α的能力，(B)它们具有很高的LD50值，在小鼠14天重复剂量毒性研究中取得了令人满意的结果。初步研究表明，当动物在X射线治疗前使用小分子肿瘤坏死因子-α调节剂(UTL-5d)进行预处理时，肝脏损伤似乎有所减轻。这一初步研究表明：(1)肿瘤坏死因子-α在肝脏损伤中起重要作用，(2)一种UTL化合物可降低肿瘤坏死因子-α水平，可能是一种潜在的肝脏辐射保护剂。这项SBIR第一阶段研究的目标是验证使用我们的肿瘤坏死因子-α调节剂来减少辐射治疗小鼠肝脏损害的可行性。在这项第一阶段研究获得批准后，将进行这项第一阶段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)为每种制剂开发并验证一种高效液相色谱方法；(3)进行动物实验，以确认UTL化合物的辐射防护作用；(4)分析肿瘤坏死因子-α水平，并试图将肿瘤坏死因子-α水平降低与肝脏损害联系起来；(5)进行辐射剂量增加研究。最终目标是开发一种与放射治疗相结合的放射防护药物。

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.