TNF-a modulator as a radioprotector in liver 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-a levels in liver by radiation is an indirectly effect of radiation treatment; high levels of TNF-a appeared to cause liver damages. The applicant organization has a series of patented small-molecules TNF-a modulators. Out of these compounds, UTL-5b, -5d and -5g have been selected due to (a) their ability to modulate TNF-a 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-a modulator (UTL-5d) before an X-ray treatment, liver damages appeared to be reduced. This preliminary study indicates that (1) TNF-a plays an important role in damaging the liver, and (2) a UTL-compound lowered TNF-a 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-a 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-a levels and attempt to correlate the reduction of TNF-a 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
