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Title: Diagnostic Microdosing Approach to Study Gemcitabine Resistance

Abstract

Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. In this paper, 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. Finally, these results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.

Authors:
 [1];  [1];  [2];  [1];  [3];  [4];  [3];  [5];  [2];  [2]
+ Show Author Affiliations
  1. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology
  2. Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division
  4. Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  5. Univ. of California Davis Medical Center, Sacramento, CA (United States). Dept. of Urology
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Univ. of California Davis, Sacramento, CA (United States); Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); Dept. of Veterans Affairs (VA) (United States)
OSTI Identifier:
1438650
Report Number(s):
LLNL-JRNL-737043
Journal ID: ISSN 0893-228X
Grant/Contract Number:  
AC52-07NA27344; RO1-CA155642; 5T32CA108459; 8P41GM103483; HHSN261201000133C; HHSN261201200048C; HHSN261201200084C; I01BX001784
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 29; Journal Issue: 11; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Scharadin, Tiffany M., Zhang, Hongyong, Zimmermann, Maike, Wang, Sisi, Malfatti, Michael A., Cimino, George D., Turteltaub, Kenneth, de Vere White, Ralph, Pan, Chong-xian, and Henderson, Paul T. Diagnostic Microdosing Approach to Study Gemcitabine Resistance. United States: N. p., 2016. Web. doi:10.1021/acs.chemrestox.6b00247.
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Scharadin, Tiffany M., Zhang, Hongyong, Zimmermann, Maike, Wang, Sisi, Malfatti, Michael A., Cimino, George D., Turteltaub, Kenneth, de Vere White, Ralph, Pan, Chong-xian, & Henderson, Paul T. Diagnostic Microdosing Approach to Study Gemcitabine Resistance. United States. https://doi.org/10.1021/acs.chemrestox.6b00247
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Scharadin, Tiffany M., Zhang, Hongyong, Zimmermann, Maike, Wang, Sisi, Malfatti, Michael A., Cimino, George D., Turteltaub, Kenneth, de Vere White, Ralph, Pan, Chong-xian, and Henderson, Paul T. Thu . "Diagnostic Microdosing Approach to Study Gemcitabine Resistance". United States. https://doi.org/10.1021/acs.chemrestox.6b00247. https://www.osti.gov/servlets/purl/1438650.
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@article{osti_1438650,
title = {Diagnostic Microdosing Approach to Study Gemcitabine Resistance},
author = {Scharadin, Tiffany M. and Zhang, Hongyong and Zimmermann, Maike and Wang, Sisi and Malfatti, Michael A. and Cimino, George D. and Turteltaub, Kenneth and de Vere White, Ralph and Pan, Chong-xian and Henderson, Paul T.},
abstractNote = {Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. In this paper, 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. Finally, these results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.},
doi = {10.1021/acs.chemrestox.6b00247},
journal = {Chemical Research in Toxicology},
number = 11,
volume = 29,
place = {United States},
year = {Thu Sep 22 00:00:00 EDT 2016},
month = {Thu Sep 22 00:00:00 EDT 2016}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acs.chemrestox.6b00247
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    Works referencing / citing this record:

    Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science
    journal, May 2019

    • Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A.
    • Toxics, Vol. 7, Issue 2
    • DOI: 10.3390/toxics7020027
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