Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions

Ductal pancreatic adenocarcinoma is associated with a very poor prognosis and most patients are given palliative care. Chemotherapy in the form of gemcitabine has been found to reduce disease-related pain, and the otherwise frequently occurring weight changes, to increase Karnofsky performance status and quality of life and has also resulted in a modest improvement in survival time. The intracellular uptake of gemcitabine is dependent on nucleoside transporters, predominantly human equilibrative nucleoside transporter-1 (hENT-1), which is over-expressed in human pancreatic adenocarcinoma cells. Cellular resistance to gemcitabine can be intrinsic or acquired during gemcitabine treatment. One of the mechanisms is a decrease in hENT-1 expression. Modifications of gemcitabine not rendering it dependent on the nucleoside transporter may be a successful future mode of chemotherapy treatment, and determination of the nucleoside receptor status at the time of diagnosis could potentially also contribute to a more targeted therapy in the future.