fig2

Figure 2. The gemcitabine metabolism and its mechanism of resistance. Gemcitabine is taken into cells by nucleoside transporters and converted by a series of reactions into dFCTP. It is incorporated into replicating DNA resulting in chain termination. The incorporated dFdCTP leads to dislodgement of DNA polymerase one nucleotide downstream of the dFdCTP. This extra nucleotide masks the break site and makes it imperceptible to the DNA repair enzymes leading to DNA damage^[49]; whereas dFdCDP inhibits ribonucleotide reductase (RNR) enzyme leading to reduced pools of dCTP thus creating a positive feedback loop ensuring gemcitabine incorporation. The steps affected by the resistance mechanisms are starred (*) in blue.