Pretreatment with A Small-Molecule Tumor Necrosis Factor-Alpha (TNF-a) Inhibitor, UTL-5g, Reduced Radiation-Induced Acute Liver Toxicity in Mice

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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.

Section: Effects Of Utl-5g Pretreatment On Lung Injury Induced By Irrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

UTL-5g Lowers Levels of TGF-Î² and TNF-Î± Elevated by Lung Irradiation and Does Not Affect Tumor-response to Irradiation

Brown¹,

Valeriote²,

Chen³

et al. 2014

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“…We also showed that UTL-5g could reduce the acute liver damage caused by local irradiation [21]. In addition, we showed that UTL-5g can markedly increase blood platelet counts in cisplatin-treated mice [20] indicating that UTL-5g might be effective in suppressing cisplatin-induced thrombocytopenia.…”

Section: Introductionmentioning

confidence: 96%

Enhancement of Bone Marrow CD41+ Megakaryocytes as well as Modulation of TNF-a, IL-12, and IL-5 by a Novel Small Molecule, UTL-5g, in Mice Treated with Cisplatin

Valeriote¹,

Chen²,

Media³

et al. 2015

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UTL-5g is a novel small-molecule chemoprotective agent against cisplatin-induced host cytotoxicity. Recent studies showed that UTL-5g increased the blood platelet count, which was reduced in cisplatintreated mice. In order to have a better understanding about the mechanism of action by which UTL-5g promotes platelet production, BDF1 mice were treated with or without UTL-5g after cisplatin treatment; several hematological analyses were conducted. The results showed that treatment of mice with UTL-5g alone by either i.p. injection or oral gavage markedly increased platelet counts. UTL-5g also restored bone marrow cell counts that were reduced by cisplatin treatment. Flow cytometric analysis showed that bone marrow CD41+ megakaryocytic cells were significantly increased in animals pretreated with UTL-5g before cisplatin. Measurement of secreted cytokines showed that pretreatment of UTL-5g lowered blood levels of both TNF- and IL-12 (p70) elevated by cisplatin treatment. On the other hand, pretreatment of UTL-5g raised blood levels of IL-5 that were lowered by cisplatin treatment. The results also showed that 60 mg/kg is the optimal dose of UTL-5g by oral route for the protection of bone marrow cells, CD41+ megakaryocytes, and platelets. In conclusion, this study suggests that UTL-5g (by i.p. injection or oral gavage) enhances the production of platelets by either protecting or increasing bone marrow CD41+ megakaryocytic cells at least in part; UTL-5g also modulates TNF-, IL-12 (p70), and IL-5. Taken together, these observed effects of UTL-5g on megakaryocytes and cytokines play important roles in the chemoprotective properties of UTL5g.

“…For example, UTL-5g reduces cisplatin-induced side effects by protecting kidney, liver, and platelets [6], thereby, increasing the tolerability of cisplatin [15]. In addition, UTL-5b and -5g reduce radiation-induced side effects in liver [16]. These pharmacological effects against chemotherapy/ radiation-induced side effects are different from those of leflunomide.…”

Section: Introductionmentioning

confidence: 98%

UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-? and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

Zhang¹,

Tang²,

Chen³

et al. 2014

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N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g) is a small-molecule chemoprotector against cisplatin and radioprotector against radiation. To further investigate its protective effects, we evaluated whether UTL-5g protects mice in a septic shock animal model. The two metabolites of UTL-5g, 5-methylisoxazole-3-carboxylic acid (Isox) and 2,4-dichloroaniline (DCA) were also evaluated side-by-side with UTL-5g. First, mice were pretreated with UTL-5g, Isox, and DCA before the i.p. injection of lipopolysaccharide (LPS)/D-(+)-galactosamine hydrochloride (D-Gal), respectively. Oral administration of both UTL-5g and Isox increased mouse survival while DCA did not, indicating that Isox is an active metabolite of UTL-5g while DCA is not. In the second study, mice were pretreated with UTL-5g or Isox individually by i.p. injection each at 30 mg/kg before LPS/D-Gal injection. The survival rates for both UTL-5g and Isox were better than those found for oral administration. In the third study, the same molar dose of UTL-5g and Isox by i.p. injection was used respectively and the results showed that UTL-5g had a better protective effect than Isox. In the fourth study, a protocol similar to the third study was used but blood samples were collected from the orbital plexus two hr after LPS/D-gal treatment. The results showed that UTL-5g lowered blood levels of both TNF- and TGF- elevated by LPS/D-gal. In summary, pretreatment of UTL-5g protected mice treated with LPS/D-Gal and the protection was related to the lowering of TNF- and TGF- levels elevated by LPS/D-Gal. In addition, UTL-5g appeared to be both an active drug and a prodrug wherein Isox is the active metabolite.