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Diagnostic Microdosing Approach to Study Gemcitabine Resistance.

Tiffany M Scharadin¹, Hongyong Zhang¹, Maike Zimmermann^1,2

¹Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.

Chemical Research in Toxicology

|September 23, 2016

Summary

Subtherapeutic gemcitabine microdoses incorporate into DNA, correlating with cytotoxicity. Ribonucleotide reductase M2 (RRM2) significantly mediates gemcitabine toxicity, suggesting DNA gemcitabine levels as a biomarker.

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Area of Science:

Biochemistry
Molecular Biology
Cancer Research

Background:

Gemcitabine is a chemotherapy drug that induces apoptosis by terminating DNA replication.
The relationship between low-dose gemcitabine incorporation into DNA and its cytotoxic effects is not fully understood.
Ribonucleotide reductase M2 (RRM2) is implicated as a resistance factor in chemotherapy.

Purpose of the Study:

To investigate the incorporation of subtherapeutic gemcitabine microdoses into DNA.
To determine if DNA gemcitabine levels correlate with drug cytotoxicity.
To elucidate the role of RRM2 in gemcitabine-mediated toxicity.

Main Methods:

Utilized nearly isogenic human bladder cancer cell lines.
Treated cells with various concentrations of 14C-labeled gemcitabine for 4-24 hours.
Quantified gemcitabine incorporation into DNA using accelerator mass spectrometry.
Performed mechanistic analysis to identify mediating factors of gemcitabine toxicity.

Main Results:

Gemcitabine was incorporated into DNA at levels that correlated with cytotoxicity.
RRM2 was identified as a key mediator of gemcitabine toxicity.
The study demonstrated a link between DNA gemcitabine levels and drug efficacy.

Conclusions:

Subtherapeutic gemcitabine microdoses can be incorporated into DNA, impacting cytotoxicity.
RRM2 plays a significant role in mediating gemcitabine toxicity in cancer cells.
Gemcitabine levels within DNA may serve as a predictive biomarker for gemcitabine treatment response.