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Bulletin Du Cancer Nov 2011Antimetabolites are cytotoxic agents, which have been developed for more than 50 years. Which cancer patient did not receive or will not receive 5-fluorouracil or... (Review)
Review
Antimetabolites are cytotoxic agents, which have been developed for more than 50 years. Which cancer patient did not receive or will not receive 5-fluorouracil or methotrexate during the evolution his or her disease? Antimetabolites are defined as interfering with the synthesis of the DNA constituents; they are structural analogues, either of purine and pyrimidine bases (or the corresponding nucleosides), or of folate cofactors, which are involved at several steps of purine and pyrimidine biosynthesis. Their first mechanism of action is, therefore, to induce depletion in nucleotides inducing in turn an inhibition of DNA replication. However, some of them are able to get inserted fraudulently into nucleic acids, inducing structural abnormalities leading to cell death by other mechanisms, including DNA breaks. We present in this paper, for the three classes of antimetabolites, both ancient and recent molecules as well as molecules still in clinical trials, without exhaustivity.
Topics: Antimetabolites, Antineoplastic; DNA Replication; Folic Acid Antagonists; Humans; Leukemia; Neoplasms; Purines; Pyrimidines
PubMed: 22049385
DOI: 10.1684/bdc.2011.1476 -
Cancer Cell Jul 2017Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine...
Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.
Topics: Carbon; Deoxycytidine; Digoxin; Drug Resistance, Neoplasm; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mucin-1; Pancreatic Neoplasms; Pentose Phosphate Pathway; Prognosis; Pyrimidines; Signal Transduction; Gemcitabine
PubMed: 28697344
DOI: 10.1016/j.ccell.2017.06.004 -
Cell Metabolism Jun 2019Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to...
Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cells, Cultured; Deoxycytidine; Drug Resistance, Neoplasm; Female; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancreatic Neoplasms; Pyrimidines; RAW 264.7 Cells; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 30827862
DOI: 10.1016/j.cmet.2019.02.001 -
Expert Opinion on Pharmacotherapy Oct 2021The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic...
INTRODUCTION
The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic options. In the last year, the soluble guanylate cyclase (sGC) stimulator, vericiguat, has drawn the attention of the medical community following the report of reduced clinical outcomes in patients with worsening chronic HF (WCHF).
AREAS COVERED
The authors review the available data on the mechanism of action of vericiguat (cyclic guanosine monophosphate (cGMP) pathway), its clinical development program, its role in HF management, and its future positioning in the therapeutic recommendations.
EXPERT OPINION
cGMP deficiency has deleterious effects on the heart and contributes to the progression of HF. Different molecules, including nitric oxide (NO) donors, phosphodiesterase inhibitors, and natriuretic peptides analogues, target the NO-sCG-cGMP pathway but have yielded conflicting results in HF patients. Vericiguat acts as a sGC stimulator thus targeting the NO-sGC-cGMP pathway by a different mechanism that complements the current pharmacotherapy for HF. Vericiguat has shown an additional statistical add-on therapy efficacy by reducing morbi-mortality in patients with WCHF. A better evaluation of HF severity might be an important determinant to guide the use of vericiguat among the available therapies.
Topics: Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Pyrimidines; Soluble Guanylyl Cyclase; Stroke Volume
PubMed: 34074190
DOI: 10.1080/14656566.2021.1937121 -
Molecular Microbiology Dec 2021Trichomoniasis is a common and widespread sexually-transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic...
Trichomoniasis is a common and widespread sexually-transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic pathways for purines and pyrimidines, making nucleoside metabolism a drug target. Here we report the first comprehensive investigation into purine and pyrimidine uptake by T. vaginalis. Multiple carriers were identified and characterized with regard to substrate selectivity and affinity. For nucleobases, a high-affinity adenine transporter, a possible guanine transporter and a low affinity uracil transporter were found. Nucleoside transporters included two high affinity adenosine/guanosine/uridine/cytidine transporters distinguished by different affinities to inosine, a lower affinity adenosine transporter, and a thymidine transporter. Nine Equilibrative Nucleoside Transporter (ENT) genes were identified in the T. vaginalis genome. All were expressed equally in metronidazole-resistant and -sensitive strains. Only TvagENT2 was significantly upregulated in the presence of extracellular purines; expression was not affected by co-culture with human cervical epithelial cells. All TvagENTs were cloned and separately expressed in Trypanosoma brucei. We identified the main broad specificity nucleoside carrier, with high affinity for uridine and cytidine as well as purine nucleosides including inosine, as TvagENT3. The in-depth characterization of purine and pyrimidine transporters provides a critical foundation for the development of new anti-trichomonal nucleoside analogues.
Topics: Biological Transport; Cloning, Molecular; Humans; Kinetics; Nucleoside Transport Proteins; Protozoan Proteins; Purines; Pyrimidines; Trichomonas Infections; Trichomonas vaginalis
PubMed: 34738285
DOI: 10.1111/mmi.14840 -
Angewandte Chemie (International Ed. in... Jun 2022Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that...
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu and Mn . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.
Topics: Aspartic Acid; Pyrimidines
PubMed: 35304939
DOI: 10.1002/anie.202117211 -
Current Topics in Medicinal Chemistry 2011Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have... (Review)
Review
Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.
Topics: Antimalarials; Binding Sites; Drug Design; Enzyme Inhibitors; Humans; Malaria, Falciparum; Models, Molecular; Plasmodium falciparum; Protein Binding; Protozoan Proteins; Purine Nucleosides; Purines; Pyrimidines; Pyrimidinones; Pyrroles; Substrate Specificity
PubMed: 21619511
DOI: 10.2174/156802611796575948 -
Clinical Pharmacokinetics Dec 2020Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves... (Review)
Review
Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves several metabolic steps including sequential phosphorylation to its monophosphate, diphosphate and triphosphate. The intracellularly formed nucleotides are responsible for the pharmacological effects. This review provides a comprehensive overview of the clinical studies that measured the intracellular nucleotide concentrations of pyrimidine analogues in patients with cancer. The objective was to gain more insight into the parallels between the different pyrimidine analogues considering their intracellular pharmacokinetics. For cytarabine and gemcitabine, the intracellular pharmacokinetics have been extensively studied over the years. However, for 5-fluorouracil, capecitabine, azacitidine and decitabine, the intracellular pharmacokinetics was only very minimally investigated. This is probably owing to the fact that there were no suitable bioanalytical assays for a long time. Since the advent of suitable assays, the first exploratory studies indicate that the intracellular 5-fluorouracil, azacitidine and decitabine nucleotide concentrations are very low compared with the intracellular nucleotide concentrations obtained during treatment with cytarabine or gemcitabine. Based on their pharmacology, the intracellular accumulation of nucleotides appears critical to the cytotoxicity of pyrimidine analogues. However, not many clinical studies have actually investigated the relationship between the intracellular nucleotide concentrations in patients with cancer and the anti-tumour effect. Only for cytarabine, a relationship was demonstrated between the intracellular triphosphate concentrations in leukaemic cells and the response rate in patients with AML. Future clinical studies should show, for the other pyrimidine analogues, whether there is a relationship between the intracellular nucleotide concentrations and the clinical outcome of patients. Research that examined the intracellular pharmacokinetics of cytarabine and gemcitabine focused primarily on the saturation aspect of the intracellular triphosphate formation. Attempts to improve the dosing regimen of gemcitabine were aimed at maximising the intracellular gemcitabine triphosphate concentrations. However, this strategy does not make sense, as efficient administration also means that less gemcitabine can be administered before dose-limiting toxicities are achieved. For all pyrimidine analogues, a linear relationship was found between the dose and the plasma concentration. However, no correlation was found between the plasma concentration and the intracellular nucleotide concentration. The concentration-time curves for the intracellular nucleotides showed considerable inter-individual variation. Therefore, the question arises whether pyrimidine analogue therapy should be more individualised. Future research should show which intracellular nucleotide concentrations are worth pursuing and whether dose individualisation is useful to achieve these concentrations.
Topics: Cytarabine; Deoxycytidine; Fluorouracil; Humans; Neoplasms; Phosphorylation; Prodrugs; Pyrimidines; Gemcitabine
PubMed: 33064276
DOI: 10.1007/s40262-020-00934-7 -
Clinical Pharmacokinetics May 2014Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of... (Review)
Review
Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.
Topics: Animals; Antifungal Agents; Child; Drug Interactions; Echinocandins; Humans; Polyenes; Pyrimidines; Triazoles
PubMed: 24595533
DOI: 10.1007/s40262-014-0139-0 -
Journal of the American Chemical Society Sep 2011A fluorescent ribonucleoside alphabet consisting of highly emissive purine ((th)A, (th)G) and pyrimidine ((th)U, (th)C) analogues, all derived from...
A fluorescent ribonucleoside alphabet consisting of highly emissive purine ((th)A, (th)G) and pyrimidine ((th)U, (th)C) analogues, all derived from thieno[3,4-d]pyrimidine as the heterocyclic nucleus, is described. Structural and biophysical analyses demonstrated that the emissive analogues are faithful isomorphic nucleoside surrogates. Photophysical analysis established that the nucleosides offer highly desirable qualities, including visible emission, high quantum yield, and responsiveness to environmental perturbations, traits entirely lacking in their native counterparts.
Topics: Crystallography, X-Ray; Fluorescence; Models, Molecular; Molecular Conformation; Pyrimidines; RNA; Stereoisomerism
PubMed: 21866967
DOI: 10.1021/ja206095a