title: Diagnostic Microdosing Approach to Study Gemcitabine Resistance.
abstract: Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic "microdoses" of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of14C-labeled gemcitabine for 4-24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Scharadin
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.
authors.forename: Hongyong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.|Accelerated Medical Diagnostics Incorporated , Berkeley, California 95618, United States.
authors.forename: Maike
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.
authors.forename: Sisi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Malfatti
authors.affiliation: Accelerated Medical Diagnostics Incorporated , Berkeley, California 95618, United States.
authors.forename: George D
authors.initials: GD
authors.lastname: Cimino
authors.affiliation: Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory , Livermore, California 94550, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Turteltaub
authors.affiliation: Department of Urology, University of California Davis Medical Center , Sacramento, California 95817, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: de Vere White
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.|Accelerated Medical Diagnostics Incorporated , Berkeley, California 95618, United States.
authors.forename: Chong-Xian
authors.initials: CX
authors.lastname: Pan
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.|Accelerated Medical Diagnostics Incorporated , Berkeley, California 95618, United States.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Henderson
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004260:DNA Repair; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000093542:Gemcitabine