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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 -
Cell Chemical Biology Sep 2017Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism... (Review)
Review
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
Topics: Antimetabolites; Argininosuccinate Synthase; Carbohydrate Metabolism; Fatty Acids; Glutamine; Glycolysis; Humans; Isocitrate Dehydrogenase; Metabolic Engineering; NAD; Neoplasms
PubMed: 28938091
DOI: 10.1016/j.chembiol.2017.08.028 -
American Journal of Cardiovascular... Sep 2023Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular... (Review)
Review
Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Secondary Prevention; Hypolipidemic Agents; Ezetimibe; Cardiovascular Diseases; Hypertriglyceridemia; Pharmaceutical Preparations; Angiopoietin-Like Protein 3
PubMed: 37486464
DOI: 10.1007/s40256-023-00594-5 -
International Journal of Molecular... Dec 2023Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as spp., spp.,... (Review)
Review
Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as spp., spp., , and have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects.
Topics: Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacy; Fungi; Lovastatin
PubMed: 38203637
DOI: 10.3390/ijms25010466 -
Hematology/oncology Clinics of North... Jun 2012This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate,... (Review)
Review
This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate, its cytotoxic determinants, mechanisms of resistance, and transport into and out of cells has led to the development of a new generation of antifolates, a process that continues in the laboratory and in the clinics. New approaches to folate-based cancer chemotherapy are described based on the targeted delivery of drugs to malignant cells.
Topics: Animals; Antimetabolites, Antineoplastic; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Methotrexate; Molecular Targeted Therapy; Neoplasms
PubMed: 22520983
DOI: 10.1016/j.hoc.2012.02.002 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antimetabolites; Antithyroid Agents; Carcinogens; Humans; Neoplasms; Propylthiouracil
PubMed: 21863091
DOI: No ID Found -
Current Atherosclerosis Reports Oct 2023It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid... (Review)
Review
PURPOSE OF REVIEW
It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals.
RECENT FINDINGS
The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Ezetimibe; Dyslipidemias; Drug Therapy, Combination; Atherosclerosis; Anticholesteremic Agents; Treatment Outcome
PubMed: 37715044
DOI: 10.1007/s11883-023-01142-x -
Tidsskrift For Den Norske Laegeforening... Jan 2017In 2015, more than 530 000 people were prescribed statins in Norway. Adverse effects from the musculoskeletal system as well as less specific side effects are frequently... (Review)
Review
In 2015, more than 530 000 people were prescribed statins in Norway. Adverse effects from the musculoskeletal system as well as less specific side effects are frequently reported. The extent of these contrasts with observations made in randomised controlled studies which report the prevalence of such adverse effects as being in line with placebo. Breaks from drug treatment, low doses, switching medication and use of other lipid-lowering drugs are the most relevant approaches to dealing with adverse effects.
Topics: Biological Products; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Muscular Diseases; PCSK9 Inhibitors; Risk Factors
PubMed: 28073228
DOI: 10.4045/tidsskr.16.0646 -
The American Journal of Managed Care Sep 2002Niacin is an important therapeutic option for the treatment of dyslipidemias and is the only agent currently available that favorably affects all components of the lipid... (Review)
Review
Niacin is an important therapeutic option for the treatment of dyslipidemias and is the only agent currently available that favorably affects all components of the lipid profile to a significant degree. Niacin has consistently been shown to significantly reduce levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a), while having the greatest high-density lipoprotein (HDL) cholesterol-raising effects of all available agents. Niacin has also been shown to significantly reduce coronary events and total mortality. Niacin is available in 3 formulations: immediate-release (IR), sustained-release (SR), and a newer formulation, niacin extended-release (ER), all of which differ in their pharmacokinetic, efficacy, and safety profiles. Conventional niacin therapy has notable limitations that include flushing, most often seen with IR formulations, and hepatotoxicity, associated with SR formulations. These side effects are related to the absorption rate and subsequent metabolism of niacin as delivered from the different products. Niacin ER has a delivery system allowing absorption rates intermediate to that of niacin IR and SR. As a result, niacin ER achieves the efficacy of niacin IR with a reduced incidence of flushing and without the hepatic effects seen with niacin SR. The pharmacist should be familiar with the differences among and the advantages and disadvantages of each formulation to educate patients and help them achieve the optimal therapeutic benefit of niacin while minimizing adverse effects.
Topics: Chemistry, Pharmaceutical; Clinical Trials as Topic; Humans; Hyperlipidemias; Hypolipidemic Agents; Niacin; Pharmacists; Professional Role; United States
PubMed: 12240702
DOI: No ID Found -
IUBMB Life Mar 2017Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects.... (Review)
Review
Glycolytic inhibitors are of interest therapeutically as they are effective against cancers that display increased glycolytic rate and mitochondrial defects. 2-Deoxyglucose (2-DG) is one such glycolytic inhibitor and was identified to be a competitive inhibitor of glucose. Studies from past few decades have shown that the mechanism of action of 2-DG is complex involving several metabolic and signaling pathways. Budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe are two important models for studying metabolism, cell cycle and cell signaling. These two unicellular eukaryotes are Crabtree positive yeasts exhibiting a metabolism similar to that of cancer cells. Effects of 2-DG in yeast is of interest owing to these similarities and hence yeasts have emerged as ideal model organisms to study the mode of action and resistance to 2-DG. In this review, we summarize the studies on biological effect and resistance to 2-DG in budding and fission yeasts and give an insight into its possible mechanism of action as models for understanding cancer metabolism and drugs affecting cancer progression. © 2017 IUBMB Life, 69(3):137-147, 2017.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Deoxyglucose; Drug Screening Assays, Antitumor; Energy Metabolism; Humans; Neoplasms; Schizosaccharomyces
PubMed: 28093891
DOI: 10.1002/iub.1599