title: The small-molecule TNF-alpha modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo.
abstract: We investigated a small-molecule modulator of tumor necrosis factor alpha (TNF-alpha), UTL-5g (also referred to as GBL-5g), as a potential chemoprotective agent against cisplatin-induced side effects including nephrotoxicity, hepatotoxicity and hematotoxicity. Pretreatment of UTL-5g i.p. in BDF1 mice reduced the levels of blood urea nitrogen (BUN) and creatinine induced by cisplatin treatment. The levels of both aspartate transaminase (AST) and alanine transaminase (ALT) in these animals were also reduced by UTL-5g. Pretreatment of UTL-5g did not significantly affect the number of white blood cells (WBC) under current experimental conditions, yet it markedly increased blood platelet counts by more than threefold. Therapeutic assessment in SCID mice inoculated with human HCT-15 tumor cells showed that UTL-5g did not attenuate the anti-tumor effect of cisplatin but increased the therapeutic efficacy of cisplatin. The LD50 of UTL-5g was determined to be > 2,000 mg/kg by an acute toxicity study. In summary, our studies showed that 1) UTL-5g significantly reduces nephrotoxicity and hepatotoxicity induced by cisplatin in mice, presumably by lowering the levels of TNF-alpha, 2) UTL-5g markedly increased blood platelet counts in mice and 3) UTL-5g treatment increased the therapeutic efficacy of cisplatin against HCT-15 cells inoculated in SCID mice.
authors.affiliation: 21st Century Therapeutics, Inc., Shelby Township, MI 48316, USA. jiajiushaw@gmail.com
authors.forename: JiaJiu
authors.initials: J
authors.lastname: Shaw
authors.forename: Ben
authors.initials: B
authors.lastname: Chen
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Huang
authors.forename: An-Rong
authors.initials: AR
authors.lastname: Lee
authors.forename: Joseph
authors.initials: J
authors.lastname: Media
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010976:Platelet Count; D023382:Toxicity Tests, Acute; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007555:Isoxazoles; D014409:Tumor Necrosis Factor-alpha; C559524:UTL-5g compound; D002945:Cisplatin