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International Journal of Molecular... Sep 2019Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While... (Review)
Review
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.
Topics: Animals; Deoxycytidine; Drug Resistance, Neoplasm; Genome; Humans; Pancreatic Neoplasms; Treatment Outcome; Tumor Microenvironment; Gemcitabine
PubMed: 31514451
DOI: 10.3390/ijms20184504 -
Genes Mar 2022Gemcitabine is a nucleoside analog that has been used widely as an anticancer drug for the treatment of a variety of conditions, including ovarian, bladder,... (Review)
Review
Gemcitabine is a nucleoside analog that has been used widely as an anticancer drug for the treatment of a variety of conditions, including ovarian, bladder, non-small-cell lung, pancreatic, and breast cancer. However, enzymatic deamination, fast systemic clearance, and the emergence of chemoresistance have limited its efficacy. Different prodrug strategies have been explored in recent years, seeking to obtain better pharmacokinetic properties, efficacy, and safety. Different drug delivery strategies have also been employed, seeking to transform gemcitabine into a targeted medicine. This review will provide an overview of the recent developments in gemcitabine prodrugs and their effectiveness in treating cancerous tumors.
Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Deoxycytidine; Humans; Lung Neoplasms; Prodrugs; Gemcitabine
PubMed: 35328020
DOI: 10.3390/genes13030466 -
Cancer Cell Jan 2018Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood....
Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras;LSL-Trp53;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
Topics: Adrenergic Agents; Animals; Carcinoma in Situ; Catecholamines; Cell Line, Tumor; Deoxycytidine; Mice, Transgenic; Nerve Growth Factors; Pancreatic Neoplasms; Gemcitabine
PubMed: 29249692
DOI: 10.1016/j.ccell.2017.11.007 -
JAMA Oncology Jun 2019Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall...
IMPORTANCE
Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed.
OBJECTIVE
To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017.
INTERVENTIONS
Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients.
MAIN OUTCOMES AND MEASURES
The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population.
RESULTS
Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment.
CONCLUSIONS AND RELEVANCE
Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02392637.
Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cisplatin; Deoxycytidine; Female; Humans; Male; Middle Aged; Paclitaxel; Treatment Outcome; Gemcitabine
PubMed: 30998813
DOI: 10.1001/jamaoncol.2019.0270 -
American Journal of Physiology. Cell... Feb 2023Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care... (Review)
Review
Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care chemotherapies renders its treatment particularly challenging and largely contributes to the devastating outcome. Gemcitabine, a pyrimidine antimetabolite, is a cornerstone in PDA treatment. Given the importance of gemcitabine in PDA therapy, extensive efforts are focusing on exploring mechanisms by which cancer cells evade gemcitabine cytotoxicity, but strategies to overcome them have not been translated into patient care. Here, we will introduce the standard treatment paradigm for patients with PDA, highlight mechanisms of gemcitabine action, elucidate gemcitabine resistance mechanisms, and discuss promising strategies to circumvent them.
Topics: Humans; Gemcitabine; Deoxycytidine; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 36571444
DOI: 10.1152/ajpcell.00331.2022 -
Journal of Clinical Oncology : Official... Feb 2015This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
PURPOSE
This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC).
PATIENTS AND METHODS
Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS).
RESULTS
Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2.
CONCLUSION
In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Deoxycytidine; Female; Fluorouracil; Furans; Humans; Ketones; Middle Aged; Taxoids; Young Adult
PubMed: 25605862
DOI: 10.1200/JCO.2013.52.4892 -
Journal For Immunotherapy of Cancer Nov 2020Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors,...
Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis.
BACKGROUND
Pancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis.
METHODS
The murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated.
RESULTS
In the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages.
CONCLUSION
The combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Models, Animal; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms; Macrophages; Mice; Neoplasm Metastasis; Pancreatic Neoplasms; Tumor Microenvironment; Gemcitabine
PubMed: 33188035
DOI: 10.1136/jitc-2020-001367 -
Angewandte Chemie (International Ed. in... Oct 2021Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present....
Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present. The methylation of dC to mdC is known to regulate transcriptional activity. Next to these five nucleosides, the genome, particularly of stem cells, contains three additional dC derivatives, which are formed by stepwise oxidation of the methyl group of mdC with the help of Tet enzymes. These are 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC), and 5-carboxy-dC (cadC). It is believed that fdC and cadC are converted back into dC, which establishes an epigenetic control cycle that starts with methylation of dC to mdC, followed by oxidation and removal of fdC and cadC. While fdC was shown to undergo intragenomic deformylation to give dC directly, a similar decarboxylation of cadC was postulated but not yet observed on the genomic level. By using metabolic labelling, we show here that cadC decarboxylates in several cell types, which confirms that both fdC and cadC are nucleosides that are directly converted back to dC within the genome by C-C bond cleavage.
Topics: Animals; CHO Cells; Cricetulus; DNA; Decarboxylation; Deoxycytidine; Deuterium; Genome; Mice; Nitrogen Isotopes
PubMed: 34432359
DOI: 10.1002/anie.202109995 -
Drug Discovery Today Feb 2018Gemcitabine is a nucleoside analog currently used for the treatment of various solid tumors as a single agent or in combination with other chemotherapeutic drugs. Its... (Review)
Review
Gemcitabine is a nucleoside analog currently used for the treatment of various solid tumors as a single agent or in combination with other chemotherapeutic drugs. Its use against highly aggressive brain tumors (glioblastoma) has been evaluated in preclinical and clinical trials leading to controversial results. Gemcitabine can inhibit DNA chain elongation, is a potent radiosensitizer and it can enhance antitumor immune activity, but it also presents some drawbacks (e.g., short half-life, side effects, chemoresistance). The aim of this review is to discuss the challenges related to the use of gemcitabine for glioblastoma and to report recent studies that suggest overcoming these obstacles opening new perspectives for its use in the field (e.g., gemcitabine derivatives and/or nanomedicines).
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Deoxycytidine; Glioblastoma; Humans; Nanomedicine; Radiation-Sensitizing Agents; Gemcitabine
PubMed: 29074439
DOI: 10.1016/j.drudis.2017.10.010 -
Postepy Higieny I Medycyny... Mar 2016Despite the enormous progress made over the past decades in diagnosis, treatment and prevention of many types of tumor, the survival rate for pancreatic cancer still... (Review)
Review
Despite the enormous progress made over the past decades in diagnosis, treatment and prevention of many types of tumor, the survival rate for pancreatic cancer still remains poor. Pancreatic cancer is one of the most malignant and chemotherapy-resistant tumors. That is mainly due to the lack of effective diagnosis at an early stage of tumor development and ineffective therapy. In most patients the disease is diagnosed at an advanced, metastatic stage and only 15-20% of patients are eligible for surgical removal of the tumor, which still remains the only chance for radical treatment. Studies in recent years have not yielded significant progress in the treatment of disease, and gemcitabine or its combinations with other chemotherapeutics such as erlotinib or capecitabine still remains the standard therapy. Although mechanisms of cell death induced by gemcitabine and other chemotherapeutic agents are well known, their effectiveness is limited due to the acquisition of drug resistance by pancreatic cancer cells. So far, mechanisms of resistance have been tested for mutations in many genes--the key to proper functioning of signaling pathways in cancer cells. However, recent studies suggest a significant role of the tumor microenvironment in the development and maintaining resistance to conventionally used chemotherapeutic and targeted therapies. Drug resistance of pancreatic cancer results from multiple mechanisms, which may include the following: mutations in key genes, aberrant gene expression, deregulation of key signaling pathways, apoptotic pathways, the capacity for epithelial-mesenchymal transition (EMT), increased angiogenesis, the presence of cancer stem cells or the presence of a hypoxic microenvironment inside the tumor.
Topics: Antineoplastic Agents; Apoptosis; Deoxycytidine; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Pancreatic Neoplasms; Signal Transduction; Tumor Microenvironment; Gemcitabine
PubMed: 26943314
DOI: 10.5604/17322693.1196387