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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 -
Annals of Oncology : Official Journal... May 2006Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is the most important cytidine analogue developed since cytosine arabinoside (Ara-C). The evidence of its potent... (Review)
Review
Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is the most important cytidine analogue developed since cytosine arabinoside (Ara-C). The evidence of its potent antitumor activity in a wide spectrum of in vitro and in vivo tumor models has been successfully confirmed in the clinical setting. Despite structural and pharmacological similarities to Ara-C, gemcitabine displays distinctive features of cellular pharmacology, metabolism and mechanism of action. Following influx through the cell membrane via nucleoside transporters, gemcitabine undergoes complex intracellular conversion to the nucleotides gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) responsible for its cytotoxic actions. The cytotoxic activity of gemcitabine may be the result of several actions on DNA synthesis. dFdCTP competes with deoxycytidine triphosphate (dCTP) as an inhibitor of DNA polymerase. dFdCDP is a potent inhibitor of ribonucleoside reductase, resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis and, thereby potentiating the effects of dFdCTP. dFdCTP is incorporated into DNA and after the incorporation of one more nucleotide leads to DNA strand termination. This extra nucleotide may be important in hiding the dFdCTP from DNA repair enzymes, as incorporation of dFdCTP into DNA appears to be resistant to the normal mechanisms of DNA repair. Gemcitabine can be effectively inactivated mainly by the action of deoxycytidine deaminase to 2,2'-difluorodeoxyuridine. Also, 5'-nucleotidase opposes the action of nucleoside kinases by catalysing the conversion of nucleotides back to nucleosides. Additional sites of action and self-potentiating effects have been described. Evidence that up- or down-regulation of the multiple membrane transporters, target enzymes, enzymes involved in the metabolism of gemcitabine and alterations in the apoptotic pathways may confer sensitivity/resistance to this drug, has been provided in experimental models and more recently also in the clinical setting. Synergism between gemcitabine and several other antineoplastic agents has been demonstrated in experimental models based on specific pharmacodynamic interactions. Knowledge of gemcitabine cellular pharmacology and its molecular mechanisms of resistance and drug interaction may thus be pivotal to a more rational clinical use of this drug in combination regimens and in tailored therapy.
Topics: Antimetabolites, Antineoplastic; Biological Transport; Deoxycytidine; Humans; Models, Biological; Neoplasms; Gemcitabine
PubMed: 16807468
DOI: 10.1093/annonc/mdj941 -
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 -
Acta Haematologica 2019
Topics: Deoxycytidine; Humans; Lymphoma, Non-Hodgkin; Salvage Therapy; Gemcitabine
PubMed: 30630165
DOI: 10.1159/000496098 -
Acta Crystallographica. Section C,... Mar 20228-Furylimidazolo-2'-deoxycytidine (ImidC), CHNO, is a fluorescent analogue of 2'-deoxycytidine, also displaying the same recognition face. As a constituent of DNA, ImidC...
8-Furylimidazolo-2'-deoxycytidine (ImidC), CHNO, is a fluorescent analogue of 2'-deoxycytidine, also displaying the same recognition face. As a constituent of DNA, ImidC forms extraordinarily strong silver-mediated self-pairs. Crystal structure determination revealed that ImidC adopts two types of disordered residues: the sugar unit and the furyl moiety. The disorder of the sugar residue amounts to an 87:13 split. The disorder of the furyl ring results from axial chirality at the C8-C2'' bond connecting the nucleobase to the heterocycle. The two atropisomers are present in unequal proportions [occupancies of 0.69 (2) and 0.31 (2)], and the nucleobase and the furyl moiety are coplanar. Considering the atomic sites with predominant occupancy, an anti conformation with χ = - 147.2 (7)° was found at the glycosylic bond and the 2'-deoxyribosyl moiety shows a C2'-endo (S, T) conformation, with P = 160.0°. A H NMR-based conformational analysis of the furanose puckering revealed that the S conformation predominates also in solution. In the solid state, two neighbouring ImidC molecules are arranged in a head-to-tail fashion, but with a notable tilt of the molecules with respect to each other. Consequently, one N-H...N hydrogen bond is found for neighbouring molecules within one layer, while a second N-H...N hydrogen bond is formed to a molecule of an adjacent layer. In addition, hydrogen bonding is observed between the nucleobase and the sugar residue. A Hirshfeld surface analysis was performed to visualize the intermolecular interactions observed in the X-ray study. In addition, the fluorescence spectra of ImidC were measured in solvents of different polarity and viscosity. ImidC responds to microenvironmental changes (polarity and viscosity), which is explained by a hindered rotation of the furyl residue in solvents of high viscosity.
Topics: Crystallography, X-Ray; DNA; Deoxycytidine; Hydrogen Bonding; Molecular Conformation
PubMed: 35245210
DOI: 10.1107/S2053229622001000 -
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 -
World Journal of Gastroenterology Sep 2012Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on...
Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Deoxycytidine; Docetaxel; Humans; Paclitaxel; Pancreatic Neoplasms; Radiotherapy; Salvage Therapy; Taxoids; Treatment Outcome; Gemcitabine
PubMed: 22969215
DOI: 10.3748/wjg.v18.i33.4457 -
The American Journal of the Medical... Jun 2021Posterior reversible encephalopathy syndrome (PRES) is a rare clinical-radiographic syndrome that has been expanding rapidly in the world of clinical medical oncology... (Review)
Review
INTRODUCTION
Posterior reversible encephalopathy syndrome (PRES) is a rare clinical-radiographic syndrome that has been expanding rapidly in the world of clinical medical oncology and hematology. In this article, we provide a unique patient case of delayed gemcitabine-induced PRES.
BRIEF CASE REPORT
A 60-year-old African American female with significant past medical history of ER+/PR+/HER2- invasive ductal carcinoma of the left breast is seen in the medical oncology clinic with vague, mild complaints of lightheadedness. She had progressed on multiple lines of chemotherapy and was ultimately switched to gemcitabine. One month after her third dose of gemcitabine, she developed acute vision loss and soon developed generalized tonic-clonic seizure. Extensive workup was unrevealing other than PRES and she slowly improved with supportive care and withdrawal of the medication.
DISCUSSION
Multiple case reports have described PRES in the context of combination chemotherapy with gemcitabine and a platinum agent in the treatment of gastrointestinal malignancies. With growing evidence, this case is consistent with the hypothesis that gemcitabine as monotherapy has a direct association with PRES. This case highlights a unique aspect in that PRES can occur at a delayed time interval, much further than the expected hours to days after the previous treatment.
Topics: Antimetabolites, Antineoplastic; Deoxycytidine; Diagnosis, Differential; Female; Humans; Middle Aged; Posterior Leukoencephalopathy Syndrome; Time Factors; Gemcitabine
PubMed: 33888263
DOI: 10.1016/j.amjms.2020.10.030 -
Archivos Espanoles de Urologia May 2018Urothelial bladder cancer is a very prevalent disease. At the time of diagnosis 70-80% of the cases present as non muscle invasive tumors. These tumors present a high... (Review)
Review
Urothelial bladder cancer is a very prevalent disease. At the time of diagnosis 70-80% of the cases present as non muscle invasive tumors. These tumors present a high recurrence and progression rates despite intravesical treatment with Bacille Calmette-Guerin and mitomycin C. Moreover, bladder conditions such as its wall impermeability and the fact that intravesical drugs are constantly being diluted by urine and eliminated do not favor the efficacy of intravesical treatment. This review analyzes new intravesical drugs such as gemcitabine or taxanes with promising results as alternative to the usual treatments or after their failure. In the same way, we detail those application vehicles designed to increase the exposition of the drug to the bladder wall and its penetration into it. We emphasize drug releasing systems, albumin nanoparticles, liposomes, magnetic nanocarriers, polymers, thermosensible hydrogels and mucoadhesives such as chitosan.
Topics: Administration, Intravesical; Antineoplastic Agents; Carcinoma, Transitional Cell; Deoxycytidine; Humans; Urinary Bladder Neoplasms; Gemcitabine
PubMed: 29745927
DOI: No ID Found