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Molecular Cancer Research : MCR Jan 2022In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of... (Review)
Review
In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of patients due to early molecular adaptation in cancer cells. A growing body of evidence suggests that a subpopulation of drug-tolerant persister cells-a reversible phenotype characterized by reduced drug sensitivity and decreased cell proliferation-maintains residual disease and may serve as a reservoir for resistant phenotypes. The survival of these residual tumor cells can be caused by reactivation of specific signaling pathways, phenotypic plasticity (i.e., transdifferentiation), epigenetic or metabolic reprogramming, downregulation of apoptosis as well as transcriptional remodeling. In this review, we discuss the molecular mechanisms that enable adaptive survival in drug-tolerant cells. We describe the main characteristics and dynamic nature of this persistent state, and highlight the current therapeutic strategies that may be used to interfere with the establishment of drug-tolerant cells, as an alternative to improve objective response to systemic therapies and delay the emergence of resistance to improve long-term survival.
Topics: Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Tolerance; Humans; Neoplasms
PubMed: 34389691
DOI: 10.1158/1541-7786.MCR-21-0038 -
Nursing Standard (Royal College of...
Topics: Drug Tolerance; Humans; Substance-Related Disorders
PubMed: 11985158
DOI: No ID Found -
Bioanalysis Nov 2019Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An...
Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An effective approach to improve drug tolerance of an NAb assay is pretreatment of samples with acid to dissociate immune complexes of NAb and drug, followed by separating NAbs from circulating drug before testing them in the assay. The acid pretreatment conditions were optimized to improve drug tolerance of cell-based and non-cell-based NAb assays. NAbs were further separated from circulating drug either through direct drug removal or purification of NAb from the sample. In addition, an integrated experimental strategy was implemented to simultaneously improve drug and its soluble target tolerance for reliable NAb assessment. The approaches described herein would enable the development of reliable NAb assays that overcome drug and its target interference for more precise and sensitive NAb assessment.
Topics: Acetic Acid; Antibodies, Neutralizing; Drug Tolerance; Hydrogen-Ion Concentration
PubMed: 31829737
DOI: 10.4155/bio-2019-0184 -
Journal of Neuroscience Research Sep 2023As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore,... (Review)
Review
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
Topics: Humans; Analgesics, Opioid; Microglia; Morphine; Drug Tolerance; Hyperalgesia; Inflammation
PubMed: 37186407
DOI: 10.1002/jnr.25199 -
Trends in Microbiology Apr 2019The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have... (Review)
Review
The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports.
Topics: Animals; Anti-Infective Agents; Bacteria; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Bacterial; Drug Tolerance; Fungi; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests
PubMed: 30448198
DOI: 10.1016/j.tim.2018.10.007 -
Journal of Immunological Methods Jun 2023Neutralizing anti-drug antibodies (ADAs) may affect safety, efficacy, and pharmacokinetic profile of a biotherapeutic drug and thus their assessment is of particular...
Neutralizing anti-drug antibodies (ADAs) may affect safety, efficacy, and pharmacokinetic profile of a biotherapeutic drug and thus their assessment is of particular importance during immunogenicity testing. Neutralizing antibody (NAb) assays typically rely on NAbs ability to block the drug-target interaction. Higher NAb concentration and/or higher binding affinity of NAb to the drug, lowers the drug-target binding interaction. However, in the presence of high concentrations of residual circulating drug, as often seen for drugs with longer half-lives or in repeat-dose studies, NAbs may exist as drug bound complexes. In direct NAb assay formats, the NAb-drug complexes present in the sample could result in the NAb being unable to block the drug-target interaction eventually leading to a false negative response. The residual free circulating drug present in the sample may bind to the target in the NAb assay thereby competing with the drug used in the assay and inhibiting the assay signal, leading to a false positive response. For traditional ADA assays, multiple approaches involving acid treatment have been described to mitigate circulating drug interference issue. Here, we report two acid-treatment approaches that utilize the Dynabeads extraction with acid dissociation and Affinity Capture Elution (ACE) principle to improve drug tolerance in NAb assays.
Topics: Antibodies, Neutralizing; Ligands; Drug Tolerance; Biological Assay
PubMed: 37116778
DOI: 10.1016/j.jim.2023.113484 -
Pharmacological Research Mar 2019
Topics: Adverse Drug Reaction Reporting Systems; Antidepressive Agents; Depressive Disorder, Major; Drug Tolerance; Humans
PubMed: 30562572
DOI: 10.1016/j.phrs.2018.12.013 -
The Journal of Pharmacology and... Apr 2022Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both...
Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both their usage in the literature and imprecise definitions in common pharmacology texts. In this perspective, I propose that these terms be distinguished by the mechanisms underlying the attenuation of drug response. Specifically, tachyphylaxis should be reserved for attenuation that occurs in response to cellular depletion, whereas tolerance should be used to describe attenuation that arises from cellular adaptations. A framework for understanding behavioral tolerance, physiologic tolerance, and dispositional tolerance as distinct phenomena is also discussed. Using this framework, a classification of drugs exhibiting attenuation of drug response with repeated administration is presented. SIGNIFICANCE STATEMENT: Distinction between tachyphylaxis and tolerance is unclear in the literature. Nonetheless, a mechanistic basis for distinguishing these important terms has practical implications for managing or preventing attenuation of drug response with repeated administration.
Topics: Drug Tolerance; Tachyphylaxis
PubMed: 35042786
DOI: 10.1124/jpet.121.000978 -
EMBO Molecular Medicine Aug 2017Considerable clinical successes have been achieved in cancer treatment since the introduction of targeted therapies. However, almost inevitably tumors develop therapy...
Considerable clinical successes have been achieved in cancer treatment since the introduction of targeted therapies. However, almost inevitably tumors develop therapy resistance, which limits durable clinical responses. Tumors are often heterogeneous, and as a result, therapy‐resistant cells are present even before the start of treatment. Resistance is commonly mediated via genetic changes. However, in this issue of , Smith (2017) report that phenotypic heterogeneity can contribute to resistance as well.
Topics: Drug Tolerance; Genotype; Humans; Phenotype
PubMed: 28694322
DOI: 10.15252/emmm.201707956 -
The Journal of Allergy and Clinical... 2018
Topics: Anaphylaxis; Chlorhexidine; Drug Tolerance; Humans
PubMed: 30390915
DOI: 10.1016/j.jaip.2018.09.001