Gemcitabine is a commonly used combination chemotherapy drug for breast, bladder, pancreas, and lung cancers. Gemcitabine (dFdC) is a nucleoside analog of deoxycytidine (dC) that becomes incorporated in the DNA of replicating cells which blocks cell proliferation and induces apoptosis. We hypothesize that by quantifying the amount of Gemcitabine incorporated into cellular DNA, we can predict the drug response of the cell. In these preliminary studies, we treat bladder and breast cancer cell lines that have varying Gemcitabine resistance levels with low doses of [14C]Gemcitabine in combination with a therapeutic dose (30 �M) or a microdose (0.3 �M) of Gemcitabine for 4 to 48 hours. The DNA is isolated from these cells and 14C levels are determined by accelerator mass spectrometry (AMS). Our results show an inverse correlation between Gemcitabine incorporation levels with cell IC50 values. Additionally, we find that the results from the microdose treatment show the same trends as those observed for the therapeutic dose, suggesting that a [14C]Gemcitabine microdose can be used to predict cell sensitivity to Gemcitabine treatment by quantitation of Gemicitabine adduct formation via AMS. Studies are currently underway to simultaneously determine the DNA incorporation or adduct level of both [14C]Gemcitabine and [14C]carboplatin from the same cells by adapting the process of DNA isolation. This combination would provide a more realistic representation of the drug combinations patients typically receive. Future studies aim to determine a threshold level of response that confers drug sensitivity that can then be incorporated into clinical trials to identify patient responders prior to a chemotherapy regimen being prescribed.

Accelerator mass spectrometry for quantifying Gemcitabine DNA incorporation and identifying Gemcitabine chemosensitivity

248th National Meeting (2014)

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