title: Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS.
abstract: ON 013100, (E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone, is a potent kinase inhibitor whose phosphate form is in Phase I clinical trials in lymphoma and acute lymphoid leukemia. The objectives were to: (a) investigate the possible presence of the glucuronide metabolite of the drug in two representative colon cancer cell lines, a drug resistant (colo-205) and a drug sensitive (colo-320); (b) quantify the glucuronide metabolite and the unchanged drug in the cells after treatment with ON 013100. The glucuronide was synthesized and a selective LC/MS/MS method was developed and validated for the characterization and quantification of the metabolite. The glucuronide metabolite (570.6 Da) was found in the drug-resistant cells upon a 1h incubation with ON 013100 (20 μg/ml). After treatment with the drug, the concentration of the metabolite gradually decreased from 0.84 μg/ml at 0 h through 0.21 μg/ml at 6h to below detection limit of 8.0 ng/ml at 9 h. No glucuronide metabolite was detected in the drug-sensitive cells. The concentrations of intact ON 013100 in the drug-resistant cells gradually decreased from 0.41 μg/ml (0 h) to 0.06 μg/ml (9 h). The corresponding concentrations of the intact drug in the drug-sensitive cells were from 2.88 μg/ml to 0.94 μg/ml.
authors.affiliation: The Tisch Cancer Institute, Division of Hematology/Medical Oncology, Dept. of Medicine, Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA. sool.cho@mssm.edu
authors.forename: Sool Yeon
authors.initials: SY
authors.lastname: Cho
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Venkat
authors.initials: V
authors.lastname: Pallela
authors.forename: Gayatri
authors.initials: G
authors.lastname: Panda
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: John
authors.initials: J
authors.lastname: Roboz
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D001593:Benzyl Compounds / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D020719:Glucuronides / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D057230:Limit of Detection; D050216:Metabolic Detoxication, Phase I; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013343:Styrenes / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D013450:Sulfones; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D020719:Glucuronides; C523044:ON013100; D047428:Protein Kinase Inhibitors; D013343:Styrenes; D013450:Sulfones