Abstract
Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer.
Highlights
Pancreatic cancer ranks fourth among the leading causes of cancer-related mortality in the Western world and is expected to surpass breast cancer, prostate cancer and colorectal cancer to become the second leading cause of cancer-related deaths after lung cancer by 2030 [1]
Since the 1997 report by Burris et al [12], gemcitabine has remained the standard of care for locally advanced and metastatic pancreatic ductal adenocarcinomas (PDAC) despite only marginal effects on patient survival
In the following two decades, gemcitabine alone or in combination with fluoropyrimidine, platinum analogues or the epidermal growth factor receptor (EGFR) inhibitor erlotinib has represented the most commonly-used front-line treatment options for PDAC therapy. This is gradually shifting with recent positive results from phase III clinical studies that established the new first-line treatment choices of FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) and the doublet of gemcitabine + nab-paclitaxel [144,147]
Summary
Pancreatic cancer ranks fourth among the leading causes of cancer-related mortality in the Western world and is expected to surpass breast cancer, prostate cancer and colorectal cancer to become the second leading cause of cancer-related deaths after lung cancer by 2030 [1]. Unlike many other cancer types, the presence of an extensive dense fibrous stroma is a hallmark of pancreatic cancer This excessive amount of scar tissue ( known as desmoplasia) that surrounds the malignant epithelial cells may account for up to 90% of the total tumor volume [13,15]. Desmoplastic stroma predominantly consists of a rich extracellular matrix (ECM) containing cancer-associated fibroblasts (CAFs), inflammatory cells, small blood vessels and a variety of cytokines and growth factors [13,15] All these components of the stroma interact closely with the malignant cells and offer potential therapeutic targets [18]. We focus primarily on the progression of pancreatic cancer chemoresistance linked to alterations in entities associated with the gemcitabine metabolism pathway
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