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

Halina Pietraszkiewicz¹, Jiajiu Shaw^2,*

¹ Henry Ford Health System, Detroit, Michigan, U.S.A.

² 21^st Century Therapeutics, Inc., Detroit, Michigan, U.S.A.

^* Corresponding author

Jiajiu Shaw

21^st Century Therapeutics, Inc.

Detroit, Michigan 48202

USA

Phone (734) 330-6052

Email: jiajiushaw@gmail.com

Abstract

UTL-5g is a small-molecule TNF-a 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.

Keywords: animal model, radiation, lung cancer, preclinical studies, radioprotector.

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