Gemcitabine metabolites cause termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic "microdoses" of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of 14C-labeled gemcitabine for 4-24 hours. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA repair protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.
Chemical research in toxicology. 2016 Sep 22 [Epub ahead of print]
Tiffany M Scharadin, Hongyong Zhang, Maike Zimmermann, Sisi Wang, Michael A Malfatti, George D Cimino, Kenneth W Turteltaub, Ralph W de Vere White, Chong-Xian Pan, Paul T Henderson