Diagnostic Microdosing Approach to Study Gemcitabine Resistance

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.

doi:10.1021/acs.chemrestox.6b00247

Title: Diagnostic Microdosing Approach to Study Gemcitabine Resistance

Journal Article · Thu Sep 22 00:00:00 EDT 2016 · Chemical Research in Toxicology

DOI:https://doi.org/10.1021/acs.chemrestox.6b00247· OSTI ID:1438650

Scharadin, Tiffany M. ^[1]; Zhang, Hongyong ^[1]; Zimmermann, Maike ^[2]; Wang, Sisi ^[1]; Malfatti, Michael A. ^[3]; Cimino, George D. ^[4]; Turteltaub, Kenneth ^[3]; de Vere White, Ralph ^[5]; Pan, Chong-xian ^[2]; Henderson, Paul T. ^[2]

Univ. of California Davis, Sacramento, CA (United States). Dept. of Internal Medicine. Division of Hematology and Oncology
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)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division
Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
Univ. of California Davis Medical Center, Sacramento, CA (United States). Dept. of Urology

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.

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Research Organization:: 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 Organization:: USDOE; National Inst. of Health (NIH) (United States); Dept. of Veterans Affairs (VA) (United States)

Grant/Contract Number:: AC52-07NA27344; RO1-CA155642; 5T32CA108459; 8P41GM103483; HHSN261201000133C; HHSN261201200048C; HHSN261201200084C; I01BX001784

OSTI ID:: 1438650

Report Number(s):: LLNL-JRNL-737043

Journal Information:: Chemical Research in Toxicology, Vol. 29, Issue 11; ISSN 0893-228X

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 7 works

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Cited By (2)

DHS (trans−4,4′-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2) Chen, Chi-Wei; Li, Yongming; Hu, Shuya Oncogene, Vol. 38, Issue 13 https://doi.org/10.1038/s41388-018-0584-6	journal	December 2018
Radiocarbon Tracers in Toxicology and Medicine: Recent Advances in Technology and Science Malfatti, Michael A.; Buchholz, Bruce A.; Enright, Heather A. Toxics, Vol. 7, Issue 2 https://doi.org/10.3390/toxics7020027	journal	May 2019

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