ReviewGemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer
Introduction
Gemcitabine is a nucleoside analog that has been used as a chemotherapeutic agent for more than 15 years. During this time gemcitabine has become the standard treatment choice for locally advanced and metastatic pancreatic cancer, for which there have been few treatment advances. Pancreatic cancer is one of the most devastating human cancers, with a median survival rate of less than 5 months after diagnosis and with under a 5% five-year survival rate even if brought under remission (Bilimoria et al., 2007). This poor prognosis is partly explained because of poor penetration of drugs into the dense and under vascularized tumour stroma (Neesse et al., 2011), a high degree of acquired chemoresistance by tumour cells and also because surgical intervention is not possible in almost 80% of patients (Vincent et al., 2011).
Gemcitabine is also used to treat a variety of solid tumors including breast, ovarian, and non-small cell lung cancer, especially when in combination with the platinum-based drugs cisplatin and carboplatin (Nagourney et al., 2008, Pfisterer et al., 2006, Reck et al., 2009). Despite its relatively broad and common use, mechanisms related to gemcitabine resistance are not well understood. A number of different cellular pathways, transcriptional factors and nucleotide metabolism enzymes have been linked to gemcitabine resistance and sensitivity.
Here the known molecular mechanisms commonly associated with gemcitabine pharmacokinetics and pharmacodynamics are reviewed with a special focus on pancreatic cancer. A better understanding of gemcitabine pharmacology is essential for developing improved treatments and ultimately for increasing patient survival in pancreatic cancer.
Section snippets
Uptake and metabolism
Gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdC) is a deoxycytidine analog with multiple modes of action inside the cell. The basics of gemcitabine metabolism are illustrated in Fig. 1. As a prodrug, dFdC must be metabolized to the active triphosphate form of gemcitabine (2′,2′-difluoro-2′-deoxycytidine triphosphate; dFdCTP). Cellular uptake of gemcitabine is mediated by a family of integral membrane proteins termed human nucleoside transporters (hNTs), which overcome the inherent barrier to
Mechanisms of action
The most important mechanism of action of gemcitabine is inhibition of DNA synthesis (Huang et al., 1991). When dFdCTP is incorporated into DNA, a single deoxynucleotide is incorporated afterwards, preventing chain elongation (Gandhi et al., 1996). This non-terminal position of gemcitabine makes DNA polymerases unable to proceed, in a process known as ‘masked chain-termination′, which also inhibits removal of gemcitabine by DNA repair enzymes (Huang et al., 1991). This process is shown in Fig. 2
Gemcitabine chemoresistance and sensitivity
Like many other drugs used in cancer chemotherapy, resistance to gemcitabine may be intrinsic, or acquired by individual patient during treatment cycles. Several mechanisms have been reported in the literature and some of these seem well established (Table 1). However, as many of these processes are complex, it can be difficult to understand precise roles and, indeed, consequences in chemoresistance. This is particularly relevant for signalling pathways involved in apoptosis, growth,
Perspectives
Gemcitabine is still the standard chemotherapeutic agent of choice to treat pancreatic cancer; with the best patient clinical outcome, and this is unlikely to change in the coming years. However, few improvements have been made in gemcitabine-based chemotherapies for pancreatic and other cancers (e.g. breast, ovarian and non-small cell lung cancer), although combination therapies are likely to emerge as realistic treatment choices, especially for pancreatic cancer. A recent phase III study of
Conclusion
Many important molecular targets and pathways related to gemcitabine chemoresistance and sensitivity are now established; however, their precise mechanisms of action are not completely understood in most cases. Different pathways and molecular interactions have been described in recent years and new roles for some relatively well-known chemoresistance markers (e.g. NF-κB) have been discovered. Gemcitabine still has clinical potential to treat a broad spectrum of human cancers, but the
Acknowledgments
Financial support was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP – Grants 2009/01303-1 and 2011/04938-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank Dr PF Long from King׳s College London and Faculdade de Ciências Farmacêuticas, Universidade de São Paulo for his critical comments.
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