Gemcitabine

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Gemcitabine (dFdC) is a pyrimidine antimetabolite analogue of cytidine.

Indications

  • Locally advanced or metastatic bladder cancer in combination with cisplatin.
  • Locally advanced or metastatic adenocarcinoma of the pancreas.
  • Locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with cisplatin usually
  • Locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin
  • Unresectable, locally recurrent or metastatic breast cancer who have relapsed (after anthracyclines), in combination with paclitaxel

Pharmacology

Gemcitabine is metabolised intracellularly by nucleoside kinase to the active diphosphate and triphosphate (dFdCTP). It inhibits DNA synthesis by two mechanisms of action:

  1. Inhibits ribonucleotide reductase, which is uniquely responsible for producing the deoxynucleoside triphosphates for DNA synthesis. Inhibition reduces in particular dCTP
  2. Competition with dCTP for incorporation into DNA (self-potentiation)
    • The reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to repair the growing DNA strands so after gemcitabine is incorporated into DNA, only one additional nucleotide can be added to the growing DNA strands. This causes masked chain termination in further DNA synthesis and induction of apoptosis.