ABSTRACT
PURPOSE: UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice. MATERIALS AND METHODS: BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored. RESULTS: UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin. CONCLUSIONS: In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.
Subject(s)
Antineoplastic Agents/toxicity , Cisplatin/toxicity , Isoxazoles/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Body Weight/drug effects , Cisplatin/administration & dosage , Dose-Response Relationship, Drug , Female , Injections, Intraperitoneal , Maximum Tolerated Dose , Mice , Survival Rate , Time Factors , Weight Loss/drug effectsABSTRACT
The isolation and structure elucidation of three new secondary metabolites, chaetoglobosin-510 (1), -540 (2), and -542 (3), are described. These compounds were produced by cultures of the marine-derived fungus Phomopsis asparagi, challenged with the known F-actin inhibitor jasplakinolide. Chaetoglobosin-542 (3) displayed antimicrofilament activity and was cytotoxic toward murine colon and leukemia cancer cell lines.
Subject(s)
Ascomycota/chemistry , Depsipeptides/pharmacology , Indoles/isolation & purification , Animals , Indole Alkaloids , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , PoriferaABSTRACT
Twenty three side chain analogs of the crambescidin alkaloids were prepared from the corresponding pentacyclic zwitterionic core acid. In the crambescidin 800 and 657 series, potency increased with increasing chain length. In addition, substantial variations in tumor selectivity with structure were seen. Crambescidin analogs having short, nonpolar side chains were identified for the first time as promising anticancer agents.
