title: Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice.
abstract: We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [14C]carboplatin or [14C]gemcitabine and the resulting drug-DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. Mol Cancer Ther; 16(2); 376-87. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California.|Accelerated Medical Diagnostics Incorporated, Berkeley, California.
authors.forename: Maike
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California.
authors.forename: Si-Si
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California.
authors.forename: Hongyong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California.
authors.forename: Tzu-Yin
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Malfatti
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Kurt
authors.initials: K
authors.lastname: Haack
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Ted
authors.initials: T
authors.lastname: Ognibene
authors.affiliation: The Jackson Laboratory, Sacramento, California.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Yang
authors.affiliation: The Jackson Laboratory, Sacramento, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Airhart
authors.affiliation: Lawrence Livermore National Laboratory, Livermore, California.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Turteltaub
authors.affiliation: Accelerated Medical Diagnostics Incorporated, Berkeley, California.
authors.forename: George D
authors.initials: GD
authors.lastname: Cimino
authors.affiliation: Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, California.
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.affiliation: Division of Hematology and Oncology, UCLA Medical Center, Los Angeles, California.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Drakaki
authors.affiliation: Department of Urology, UCLA Medical Center, Los Angeles, California.
authors.forename: Karim
authors.initials: K
authors.lastname: Chamie
authors.affiliation: Department of Urology, University of California Davis, Sacramento, California.
authors.forename: Ralph
authors.initials: R
authors.lastname: de Vere White
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California. phenderson@ucdavis.edu cxpan@ucdavis.edu.|Department of Urology, University of California Davis, Sacramento, California.|VA Northern California Health Care System, Mather, California.
authors.forename: Chong-Xian
authors.initials: CX
authors.lastname: Pan
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology and UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, California. phenderson@ucdavis.edu cxpan@ucdavis.edu.|Accelerated Medical Diagnostics Incorporated, Berkeley, California.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Henderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015415:Biomarkers; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000097:blood / Q000378:metabolism; D004260:DNA Repair; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D018736:DNA Adducts; C096276:carboplatin-DNA adduct; D003841:Deoxycytidine; D010984:Platinum; D016190:Carboplatin; D000093542:Gemcitabine