UTL-5g Lowers Levels of TGF-β and TNF-α Elevated by Lung Irradiation and Does Not Affect Tumor-response to Irradiation

Abstract

UTL-5g is a small-molecule TNF- inhibitor having chemoprotective and liver radioprotective effects. We investigated the effects of UTL-5g on lung irradiated mice and whether UTL-5g affects tumor responses to radiotherapy. C57BL/6 mice were individually treated with UTL-5g at 15, 30, and 60 mg/kg and amifostine (200 mg/kg) by i.p. injection 30 min prior to lung irradiation of 6 Gy (daily x 5). Two mice in the amifostine group died within 8 wks. At the first time point (8 wks), the plasma levels of TGF-β elevated by irradiation were significantly reduced by UTL-5g at 60 mg/kg (p<0.05). For the second time point (5 months), elevated levels of TNF-α in lung tissue from the irradiated group were suppressed by UTL-5g in a dose-dependent manner and was statistically significant at 60 mg/kg (p<0.05). Amifostine also showed a similar effect but at a much higher dose, 200 mg/kg (p <0.05). Incidentally, it was observed that UTL-5g delayed the radiation-induced hair-discoloration significantly ( >60 days after lung irradiation). The results indicate that UTL-5g may protect melanocytes against radiation-induced injury. Next, the effects of UTL-5g on tumor response were investigated in CD-1 nu/nu athymic nude mice bearing intramuscular A549 tumors (human non-small cell lung carcinoma) implanted in the right gastrocnemius muscle. Animals were treated with UTL-5g (30 mg/kg i.p.) 30 min prior to or after irradiation (5 Gy) daily for five days. The results showed that UTL-5g did not protect tumor from radiation damage. These observations suggest that UTL-5g may be lung radioprotective and thus, warranted further investigation.

Decreasing the Toxicity of Radiation Therapy: Radioprotectors and Radiomitigators Being Developed by the National Cancer Institute Through Small Business Innovation Research Contracts

“…Current progress and pertinent Phase I and II milestones for the SBIR funded research contracts that advanced to Phase II are summarized in Table 2. [4][5][6][7][8][9][10][11][12] In the overall cohort of SBIR contracts for protectors and mitigators, the rate of transitioning from Phase I to Phase II funding was 42% (5/12). All three submitted Fast-Track applications successfully completed Phase I milestones and transitioned to SBIR Phase II funding, while 22% (2/9) of the standard Phase I contracts advanced to Phase II funding.…”

The Active Metabolite of UTL-5g, 5-Methylisoxazole-3-Carboxylic Acid, is Anti-Inflammatory and Reduces Doxorubicin-Induced Cardiac Toxicity

“…UTL-5g lowered levels of TNF-α (in both blood and liver) elevated by radiation and reduced the acute liver toxicity induced by localized liver irradiation [3]. In a lung radioprotection study, UTL-5g lowered levels of TNF-α in lung and TGF-β in blood, both were elevated by radiation [4].…”

A liquid chromatography with tandem mass spectrometry method for simultaneous determination of UTL-5g and its metabolites in human plasma

“…UTL-5g also increased the tolerability of cisplatin in mice and increased the survival rates of mice treated with high doses of cisplatin treatment [1]; this observation further corroborated its chemoprotective effects against the toxicity of cisplatin. As to radioprotection, UTL-5g reduced the acute liver injury induced by radiation in vivo [3]; in addition, UTL-5g lowered levels of both TGF-β in blood and TNF-α in lung, which were elevated by lung irradiation, but did not affect tumor-response to radiation [4]. These results indicate that UTL-5g is an active agent that reduces a high level of toxicity indicator caused by cisplatin or radiation.…”