Diagnostic Microdosing Approach to Study Gemcitabine Resistance

Tiffany M. Scharadin, Hongyong Zhang, Maike Zimmermann, Sisi Wang, Michael A. Malfatti, George D. Cimino, Ken W Turteltaub, Ralph W deVere White, Chong-Xian Pan, Paul Henderson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 14C-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.

Original languageEnglish (US)
Pages (from-to)1843-1848
Number of pages6
JournalChemical Research in Toxicology
Volume29
Issue number11
DOIs
StatePublished - Nov 21 2016

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gemcitabine
DNA
Cytotoxicity
Pharmaceutical Preparations
Chemotherapy
R Factors
Biomarkers
Metabolites
DNA Replication
Urinary Bladder Neoplasms
Particle accelerators
Mass spectrometry
Toxicity
Mass Spectrometry
Cells
Apoptosis
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Toxicology

Cite this

Scharadin, T. M., Zhang, H., Zimmermann, M., Wang, S., Malfatti, M. A., Cimino, G. D., ... Henderson, P. (2016). Diagnostic Microdosing Approach to Study Gemcitabine Resistance. Chemical Research in Toxicology, 29(11), 1843-1848. https://doi.org/10.1021/acs.chemrestox.6b00247

Diagnostic Microdosing Approach to Study Gemcitabine Resistance. / Scharadin, Tiffany M.; Zhang, Hongyong; Zimmermann, Maike; Wang, Sisi; Malfatti, Michael A.; Cimino, George D.; Turteltaub, Ken W; deVere White, Ralph W; Pan, Chong-Xian; Henderson, Paul.

In: Chemical Research in Toxicology, Vol. 29, No. 11, 21.11.2016, p. 1843-1848.

Research output: Contribution to journalArticle

Scharadin TM, Zhang H, Zimmermann M, Wang S, Malfatti MA, Cimino GD et al. Diagnostic Microdosing Approach to Study Gemcitabine Resistance. Chemical Research in Toxicology. 2016 Nov 21;29(11):1843-1848. https://doi.org/10.1021/acs.chemrestox.6b00247
Scharadin, Tiffany M. ; Zhang, Hongyong ; Zimmermann, Maike ; Wang, Sisi ; Malfatti, Michael A. ; Cimino, George D. ; Turteltaub, Ken W ; deVere White, Ralph W ; Pan, Chong-Xian ; Henderson, Paul. / Diagnostic Microdosing Approach to Study Gemcitabine Resistance. In: Chemical Research in Toxicology. 2016 ; Vol. 29, No. 11. pp. 1843-1848.
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