Open AccessDiagnostic Microdosing Approach to Study Gemcitabine Resistance
Author(s) -
Tiffany M. Scharadin,
Hongyong Zhang,
Maike Zimmermann,
Sisi Wang,
Michael Malfatti,
George D. Cimino,
Kenneth W. Turteltaub,
Ralph de Vere White,
Chong Xian Pan,
Paul Henderson
Publication year - 2016
Publication title -
chemical research in toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.031
H-Index - 156
eISSN - 1520-5010
pISSN - 0893-228X
DOI - 10.1021/acs.chemrestox.6b00247
Subject(s) - gemcitabine , cytotoxicity , chemistry , dna replication , deoxycytidine , drug resistance , pharmacology , biomarker , drug , dna , dna damage , chemotherapy , cancer research , biology , biochemistry , genetics , in vitro
Gemcitabine metabolites cause the 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 14 C-labeled gemcitabine for 4-24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.