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Biochemical Mechanism of Gemcitabine

The biochemical mechanism of Gemcitabine and the issues that arise with its use as an anti-cancer drug

In 2016, lung and breast cancers were each within the top 10 causes of deaths in high-income countries as well as colon and rectum cancers (Who.int, 2019). Cancer’s status as one of the leading causes of death, is the reason why anti-cancer drugs such as gemcitabine need to be studied meticulously in order to improve the efficacy of cancer treatment. Further studies on the uptake of gemcitabine and its mechanism of action may allow us to devise possible solutions that make chemotherapy more effective.

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Gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdC) was first approved by the Food and Drug Administration (FDA) in 1996 as a first-line treatment for stage II, stage III and metastatic stage IV pancreatic adenocarcinoma. Clinical studies indicate that gemcitabine has a relatively low toxicity with myelosuppression as the primary dose-limiting concern. In addition to this, gemcitabine has displayed anti-tumour activity in cancers such as pancreatic cancer, lung cancer, breast and ovarian cancer. It is known that gemcitabine is an antimetabolite drug and figure 1. demonstrates that it is a nucleoside analog of deoxycytidine (Barton-Burke, 1999).

Figure 1. Structural diagrams of deoxycytidine and its nucleoside analog gemcitabine.

Source: Adapted from (Mini et al., 2006)

Gemcitabine may be delivered into the body intravenously together with other anti-cancer drugs such as fluorouracil and cisplatin, or it may be administered as a solo chemotherapeutic agent. Cellular uptake of gemcitabine is largely dependent on a class of intramembrane proteins referred to as human nucleoside transporters (hNTs), this is due to the hydrophilic nature of gemcitabine. This family of hNTs can be further sub-divided into two distinct groups which are determined by their transport mechanism, these are termed equilibrative hNTs (hENTs) and concentrative hNTs (hCNTs). Gemcitabine transport across cellular plasma membranes is mediated by hENT1 (SLC29A1), hENT2 (SLC29A2), hCNT1 (SLC28A1) and hCNT3 (SLC28A3) (Alvarellos et al., 2014; de Sousa Cavalcante and Monteiro, 2014).

Once within the target cells, gemcitabine must be phosphorylated into the pharmacologically active form by a series of kinases. However, approximately 90% of the administered gemcitabine is deaminated by cytidine deaminase (CDA) into the inactive form 2’2’ difluorodeoxyuridine (dFdU). The rest of the remaining gemcitabine is phosphorylated in a rate-limiting step, catalysed by deoxycytidine kinase (DCK), into gemcitabine monophosphate (dFdCMP). The monophosphate form of gemcitabine is also susceptible to deactivation by deoxycytidine deaminase (DCTD) forming dFdUMP; or dFdCMP may be dephosphorylated back to dFdC by 5’ nucleotidases (NT5C). Despite these deactivation steps, dFdCMP must be further phosphorylated to form gemcitabine diphosphate (dFdCDP), this step is catalysed by UMP/CMP kinase (CMPK1). Finally, dFdCDP is phosphorylated once more by nucleoside-diphosphate kinase (NDPK, NME) forming the biochemically active gemcitabine triphosphate (dFdCTP) (Alvarellos et al., 2014). Figure 2. depicts this intracellular progression and regulation of gemcitabine.

Figure 2. A schematic diagram of the metabolic advancement of gemcitabine within a cell.

Source: Adapted from (Alvarellos et al., 2014).

Figure 2. also illustrates dFdCDP inhibiting ribonucleotide reductase 1 (RRM1) which subsequently diminishes dNTP reservoirs; due to RRM1 being involved in the formation of dNTP via the nucleoside salvage pathway. Depleting levels of dNTP ultimately encourages gemcitabine uptake and DCK activity whilst decreasing DCTD activity (Alvarellos et al., 2014). As well, dFdCTP directly inhibits DCTD and this is referred to as self-potentiation (shown in figure 2.) (de Sousa Cavalcante and Monteiro, 2014).

Primarily, dFdCTP acts by inserting itself into elongating DNA and allowing local dNTP to be adjacently incorporated in a step described as masked chain-termination. During this process, polymerases are incapable of functioning normally discontinuing DNA elongation. The addition of a neighbouring dNTP is key for the obstruction of gemcitabine removal by base-excision repair. These events are responsible for the cease in DNA synthesis and cellular apoptosis, which are depicted in figure 3. (de Sousa Cavalcante and Monteiro, 2014).

Figure 3. A schematic diagram of the incorporation of dFdCTP into DNA during elongation resulting in masked chain-termination and eventually apoptosis.

Alternatively, apoptosis may also be induced by caspase signalling in which p38 mitogen-activated protein kinase (MAPK) is activated by gemcitabine. However, inhibition of a p38-MAPK effector, MAPK-activated protein kinase (MK2), allowed osteosarcoma cells to endure gemcitabine treatment with the aid of translesion polymerase activity (de Sousa Cavalcante and Monteiro, 2014).




  • Alvarellos, M., Lamba, J., Sangkuhl, K., Thorn, C., Wang, L., Klein, D., Altman, R. and Klein, T. (2014). PharmGKB summary. Pharmacogenetics and Genomics, 24(11), pp.564-574.
  • Barton-Burke, M. (1999). Gemcitabine: A pharmacologic and clinical overview. Cancer Nursing, 22(2), pp.176-183.
  • de Sousa Cavalcante, L. and Monteiro, G. (2014). Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. European Journal of Pharmacology, 741, pp.8-16.
  • Mini, E., Nobili, S., Caciagli, B., Landini, I. and Mazzei, T. (2006). Cellular pharmacology of gemcitabine. Annals of Oncology, 17(5), pp.7-12.


  • Who.int. (2019). The top 10 causes of death. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death [Accessed 12 Feb. 2019].


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