Abstract
Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-to-mesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.
Highlights
Gemcitabine [2’,2’-difluoro-2’-deoxycytidine], was first described by Eli Lilly and Company in 1986[1] and is the most important deoxycytidine nucleoside analogue with fluorine substituents at the 2’www.cdrjournal.comSaiki et al
The resulting dFdCTP is incorporated into DNA and the DNA strand synthesis is terminated after incorporation of another nucleotide, hiding dFdCTP from DNA repair enzymes[5]. dFdCTP is incorporated into RNA[6,7], and sensitivity to gemcitabine is related to differences in RNA incorporation[8]
RNA incorporation of gemcitabine may play an important role in its activity. dFdCDP is an effective inhibitor of ribonucleoside-diphosphate reductase, an enzyme that transforms CDP into dCDP; this results in a decrease of the dCTP pool
Summary
Gemcitabine [2’,2’-difluoro-2’-deoxycytidine (dFdC)], was first described by Eli Lilly and Company in 1986[1] and is the most important deoxycytidine nucleoside analogue with fluorine substituents at the 2’www.cdrjournal.comSaiki et al. The majority of studies on patients with resected pancreatic cancer have suggested that high expression of this hENT1 may be predictive of improved survival in patients treated with gemcitabine[22,23,24]. Disrupted expression of hENT2 on the plasma membrane causes impaired uptake of gemcitabine, resulting in acquired chemoresistance of pancreatic cancer cells[25].
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