Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective

Abstract

Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology.

Keywords: 2′,2′-difluoro-2′-deoxyuridine; Cytidine deaminase; Gemcitabine; Gemcitabine prodrugs; Pharmacogenetics; Polymorphisms.

Fig. 1

Gemcitabine (dFdC) patterns and mechanisms of action. CDA cytidine deaminase, dCK deoxycytidine kinase, NMPK nucleotide monophosphate kinase, NDPK nucleotide diphosphate kinase, hENT1 human equilibrative nucleoside transporter-1, hCNT3 human concentrative nucleoside transporter-3. In cancer cells, genetic polymorphisms affecting membrane transporters, activating and deactivating enzymes and pharmacological targets such as ribonucleotide reductase, are all associated with treatment efficacy