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

Here, 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.
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [3] ;  [3] ;  [3] ;  [4] ;  [4] ;  [3] ;  [5] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [1]
  1. Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology; Accelerated Medical Diagnostics Inc., Berkely, CA (United States)
  2. Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Jackson Lab., Sacramento, CA (United States)
  5. Accelerated Medical Diagnostics Inc., Berkely, CA (United States)
  6. Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine
  7. Univ. of California, Davis, CA (United States). School of Medicine, Dept. of Biochemistry and Molecular Medicine
  8. Univ. of California, Los Angeles, CA (United States). Medical Center, Dept. of Urology
  9. Univ. of California Davis, Sacramento, CA (United States). Dept. of Urology
  10. Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology; Univ. of California Davis, Sacramento, CA (United States). Dept. of Urology; VA Northern California Health Care System, Mather, CA (United States)
Publication Date:
Report Number(s):
LLNL-JRNL-703556
Journal ID: ISSN 1535-7163
Grant/Contract Number:
AC52-07NA27344; CA93373; P41 RR13461; HHSN261201000133C; HHSN261201200048C; P30CA093373
Type:
Accepted Manuscript
Journal Name:
Molecular Cancer Therapeutics
Additional Journal Information:
Journal Volume: 16; Journal Issue: 2; Journal ID: ISSN 1535-7163
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; diagnostic microdosing; chemotherapy resistance; bladder cancer; accelerator mass spectrometry; patient derived xenografts
OSTI Identifier:
1410044

Zimmermann, Maike, Wang, Si-Si, Zhang, Hongyong, Lin, Tzu-yin, Malfatti, Michael, Haack, Kurt, Ognibene, Ted, Yang, Hongyuan, Airhart, Susan, Turteltaub, Kenneth W., Cimino, George D., Tepper, Clifford G., Drakaki, Alexandra, Chamie, Karim, de Vere White, Ralph, Pan, Chong-xian, and Henderson, Paul T.. Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice. United States: N. p., Web. doi:10.1158/1535-7163.MCT-16-0381.
Zimmermann, Maike, Wang, Si-Si, Zhang, Hongyong, Lin, Tzu-yin, Malfatti, Michael, Haack, Kurt, Ognibene, Ted, Yang, Hongyuan, Airhart, Susan, Turteltaub, Kenneth W., Cimino, George D., Tepper, Clifford G., Drakaki, Alexandra, Chamie, Karim, de Vere White, Ralph, Pan, Chong-xian, & Henderson, Paul T.. Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice. United States. doi:10.1158/1535-7163.MCT-16-0381.
Zimmermann, Maike, Wang, Si-Si, Zhang, Hongyong, Lin, Tzu-yin, Malfatti, Michael, Haack, Kurt, Ognibene, Ted, Yang, Hongyuan, Airhart, Susan, Turteltaub, Kenneth W., Cimino, George D., Tepper, Clifford G., Drakaki, Alexandra, Chamie, Karim, de Vere White, Ralph, Pan, Chong-xian, and Henderson, Paul T.. 2016. "Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice". United States. doi:10.1158/1535-7163.MCT-16-0381. https://www.osti.gov/servlets/purl/1410044.
@article{osti_1410044,
title = {Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice},
author = {Zimmermann, Maike and Wang, Si-Si and Zhang, Hongyong and Lin, Tzu-yin and Malfatti, Michael and Haack, Kurt and Ognibene, Ted and Yang, Hongyuan and Airhart, Susan and Turteltaub, Kenneth W. and Cimino, George D. and Tepper, Clifford G. and Drakaki, Alexandra and Chamie, Karim and de Vere White, Ralph and Pan, Chong-xian and Henderson, Paul T.},
abstractNote = {Here, 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.},
doi = {10.1158/1535-7163.MCT-16-0381},
journal = {Molecular Cancer Therapeutics},
number = 2,
volume = 16,
place = {United States},
year = {2016},
month = {11}
}