journal contribution posted on 2023-04-03, 14:47 authored by Maike Zimmermann, Si-Si Wang, Hongyong Zhang, Tzu-yin Lin, Michael Malfatti, Kurt Haack, Ted Ognibene, Hongyuan Yang, Susan Airhart, Kenneth W. Turteltaub, George D. Cimino, Clifford G. Tepper, Alexandra Drakaki, Karim Chamie, Ralph de Vere White, Chong-xian Pan, Paul T. Henderson
Chemical structures, patient data, mouse survival curves, additional biomarker data
American Cancer Society
Knapp Family Fund
VA Career Development Award-2
National Center for Research Resources
ARTICLE ABSTRACTWe 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.