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

Journal Article · Wed Nov 30 00:00:00 EST 2016 · Molecular Cancer Therapeutics

DOI:https://doi.org/10.1158/1535-7163.MCT-16-0381· OSTI ID:1410044

Zimmermann, Maike ^[1]; Wang, Si-Si ^[2]; Zhang, Hongyong ^[2]; Lin, Tzu-yin ^[2]; Malfatti, Michael ^[3]; Haack, Kurt ^[3]; Ognibene, Ted ^[3]; Yang, Hongyuan ^[4]; Airhart, Susan ^[4]; Turteltaub, Kenneth W. ^[3]; Cimino, George D. ^[5]; Tepper, Clifford G. ^[6]; Drakaki, Alexandra ^[7]; Chamie, Karim ^[8]; de Vere White, Ralph ^[9]; Pan, Chong-xian ^[10]; Henderson, Paul T. ^[1]

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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)

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.

• Research Organization: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
• Sponsoring Organization: USDOE; National Institutes of Health (NIH)
• Grant/Contract Number: AC52-07NA27344; CA93373; P41 RR13461; HHSN261201000133C; HHSN261201200048C; P30CA093373
• OSTI ID: 1410044
• Report Number(s): LLNL-JRNL-703556
• Journal Information: Molecular Cancer Therapeutics, Vol. 16, Issue 2; ISSN 1535-7163
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
diagnostic microdosing
chemotherapy resistance
bladder cancer
accelerator mass spectrometry
patient derived xenografts