Pharmacology: Pharmacodynamics: Cellular metabolism and mechanism of action: Gemcitabine (dFdc) is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic action of Gemcitabine appears to be due to inhibition of DNA synthesis by two actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase which is uniquely responsible for catalysing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general and especially in that of dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation). Likewise, a small amount of Gemcitabine may also be incorporated into RNA. Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon is essentially unable to remove Gemcitabine and repair the growing DNA strands. After Gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition, there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, Gemcitabine then appears to induce the programmed cellular death process known as apoptosis.
Sign Out
