Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Mol Cancer Ther. 2017 Feb;16(2):376-387. doi: 10.1158/1535-7163.MCT-16-0381. Epub 2016 Nov 30.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Biomarkers*
  • Carboplatin / administration & dosage
  • Carboplatin / adverse effects
  • Carboplatin / blood
  • Carboplatin / metabolism
  • Carboplatin / pharmacokinetics
  • Cell Line, Tumor
  • DNA Adducts* / blood
  • DNA Adducts* / metabolism
  • DNA Repair
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacokinetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Female
  • Humans
  • Mass Spectrometry
  • Mice
  • Mutation
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Platinum / administration & dosage
  • Platinum / adverse effects
  • Platinum / pharmacokinetics
  • Urinary Bladder Neoplasms / diagnosis
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers
  • DNA Adducts
  • carboplatin-DNA adduct
  • Deoxycytidine
  • Platinum
  • gemcitabine
  • Carboplatin