Abstract
Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.
Highlights
Ranking as the fourth leading cause of cancer-related mortality in western countries, pancreatic cancer is predicted to become the second leading cause of cancer-related death after lung cancer by 2030 [1]
Recent data indicate that the expression of a member of the concentrative nucleoside transporters, hCNT1, is constantly decreased in pancreatic cancer (PC) cell lines compared with normal pancreatic ductal epithelial cells, and can induce cell cycle arrest and increase cell apoptosis through non-apoptotic mechanisms and inhibit cell migration [34,35]
It is worth mentioning that Schlafen 11 (SLFN11) is inactivated in about 50% of cancer cell lines and most tumors, and cells with lower expression of SLFN11 are highly sensitive to chemotherapeutic drugs [97,98]. These results demonstrate the importance of SLFN11 in response to DNA-damaging agents (DDAs) and suggest the importance of testing SLFN11 expression as a predictive biomarker, with a potential benefit for a large number of patients with multiple cancer types treated with DDAs
Summary
Ranking as the fourth leading cause of cancer-related mortality in western countries, pancreatic cancer is predicted to become the second leading cause of cancer-related death after lung cancer by 2030 [1]. Pancreatic cancer remains a deadly malignancy, with few symptoms showing before the disease reaches its advanced stage [2]. 458,918 new cases of pancreatic cancer were found in 2018, causing 432,242 deaths [3]. Despite progress in the techniques of detecting and managing pancreatic cancer, the five-year survival rate only reaches to about 9% [3,4]. The main factors like low rate of early detection, rapid progression, the development of drug resistance, and lack of proper therapy lead to a poor prognosis of PC. Most primary pancreatic cancer patients lack corresponding clinical symptoms, and the existing screening biomarkers, such as CA19-9, have shown low sensitivity and specificity in diagnosing PC. Most primary pancreatic cancer patients lack corresponding clinical symptoms, and the existing screening biomarkers, such as CA19-9, have shown low sensitivity and specificity in diagnosing PC. [6,7]
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