• Tumor Cells
  • IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC 50 values between 0.012 and 0.298 μmol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. (aacrjournals.org)
  • After a series of design, synthesis, and biological testing, we have identified a new tubulin ligand of N -(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105), which showed a potent anticancer activity in a variety of human tumor cells in vitro and in vivo . (aacrjournals.org)
  • toxicity
  • however, use of these drugs is often associated with patient toxicity and poor tumor delivery. (hindawi.com)
  • Finally, paclitaxel (PTX)-loaded OA02-NPs exhibited superior antitumor efficacy and lower systemic toxicity profile in nude mice bearing SKOV-3 tumor xenografts, when compared with equivalent doses of nontargeted PTX-NPs as well as clinical paclitaxel formulation (Taxol). (aacrjournals.org)
  • Paclitaxel-loaded PEG 5k -CA 8 nanoparticles have been shown to exhibit superior antitumor efficacy and toxicity profile than free drug (Taxol) and paclitaxel/human serum albumin nanoaggregate (Abraxane) at equivalent paclitaxel doses, in nude mice bearing human ovarian cancer (SKOV-3) xenografts ( 6 ). (aacrjournals.org)
  • Also, the drugs can often be used at lower doses, reducing toxicity. (wikipedia.org)
  • receptor
  • Among the most important of these checkpoints is the programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) pathway, in which PD-L1 expressed by tumor or tumor-infiltrating immune cells binds to PD-1, inhibiting T-cell receptor signaling and blocking the antitumor immune response ( 2-4 ). (aacrjournals.org)
  • 2016). The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the binding strength. (fiocruz.br)
  • A detection method is used to determine the presence and extent of the ligand-receptor complexes formed, and this is usually determined electrochemically or through a fluorescence detection method. (wikipedia.org)
  • Historically, ligand binding assay techniques were used extensively to quantify hormone or hormone receptor concentrations in plasma or in tissue. (wikipedia.org)
  • Radioligands are used to measure the ligand binding to receptors and should ideally have high affinity, low non-specific binding, high specific activity to detect low receptor densities, and receptor specificity. (wikipedia.org)
  • Aside from its cofactor role for intracellular enzymes, FA also displays high affinity for the folate receptor (FR), a glycosylphosphatidyinositol-linked protein that captures its ligands from the extracellular milieu and transports them inside the cell via a non-destructive, recycling endosomal pathway. (wikipedia.org)
  • When this ligand, known to bind the FR, is added in excess of the folate conjugate, it outcompetes the conjugate, indicating that the folate conjugate specifically binds the FR, and not other receptors, in the process of receptor-mediated endocytosis. (wikipedia.org)
  • Myeloma bone disease is due to the overexpression of receptor activator for nuclear factor κ B ligand (RANKL) by bone marrow stroma. (wikipedia.org)
  • efficacy
  • However, the more extensive use of chemotherapeutic drugs such as paclitaxel is often limited by its severe side effects, including hypersensitivity reactions, myelosuppression, and neurotoxicity, which may be attributed to their nonspecific systemic organ distribution and inadequate intratumor concentrations, resulting in suboptimal efficacy ( 2, 3 ). (aacrjournals.org)
  • Combination of IG-105 with known anticancer drugs largely improved the therapeutic efficacy. (aacrjournals.org)
  • Hits from these screens are then tested in cells and then in animals for efficacy. (wikipedia.org)
  • Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy/potency, metabolic stability (to increase the half-life), and oral bioavailability. (wikipedia.org)
  • targets
  • The potential reversibility of epigenetic modifications (e.g., those that direct chromatin organization) renders the enzymes that are responsible for tumorigenic epigenetic changes important targets for drug development. (aacrjournals.org)
  • Significant improvements in assay reagents and availability of HTS-compatible readers, however, have now delivered a cost-effective, robust technology applicable to a broad range of therapeutic targets. (ddw-online.com)
  • High-throughput screening (HTS) continues to evolve in response to the changing landscape of therapeutic targets and the needs of lead discovery teams. (ddw-online.com)
  • In addition, FLT assays have now been configured for deubiquitinases, protein-protein interactions and a number of different epi-enzyme targets. (ddw-online.com)
  • In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. (fiocruz.br)
  • Protein kinases have become popular drug targets. (wikipedia.org)
  • soluble
  • Polymeric micelles represent one of the most promising nanocarriers due to their unique core-shell structure formed by amphiphilic block copolymers, which could facilitate the solublization of poorly soluble drugs and protect the drugs from degradation and metabolism. (aacrjournals.org)
  • hormonal
  • Importantly, the use of drugs (whether chemotherapy, hormonal therapy or targeted therapy) constitutes systemic therapy for cancer in that they are introduced into the blood stream and are therefore in principle able to address cancer at any anatomic location in the body. (wikipedia.org)
  • metabolism
  • however, stand-alone chemotherapy drugs suffer from numerous problems including rapid in vivo metabolism and/or excretion, inability to access and penetrate cancer cells, and nonspecific uptake by healthy cells and tissue. (hindawi.com)
  • bound
  • Some newer types are called "mix-and-measure" assays because they do not require separation of bound ligands. (wikipedia.org)
  • In this technique, drug particles are enveloped in a plasma membrane-bound vesicle. (wikipedia.org)
  • Platinum nanoparticle seeds were prepared by the decomposition of Pt2(dba)3 in tetrahydrofuran (THF) under carbon monoxide (CO). These conditions produced Pt nanoparticles with weakly bound THF and CO ligands and an approximate diameter on 1.2 nm. (wikipedia.org)
  • overexpression
  • The whole-mount Casp3 assay is optimized for analysis of fixed embryos between the 4-cell stage and 32 hr-post-fertilization and is useful for a number of applications, including analysis of zebrafish mutants and morphants, overexpression of mutant and wild-type mRNAs, and exposure to chemicals. (jove.com)
  • TRAIL
  • We describe here the development of a novel 384-well high-throughput screening (HTS) strategy for identifying potential TRAIL-sensitizing agents that act solely in a caspase-8 dependent manner. (jove.com)
  • fluorescence
  • This is also a direct assay and is not dependent on the use of fluorescence polarization (Kapuscinski, J. and Skoczyles, B., Analytical Biochem. (google.com.au)
  • Luminescence and fluorescence-based assay methods prevail in modern HTS. (ddw-online.com)
  • Although invaluable as technologies, the problem of compoundrelated assay interferences such as quenching, auto-fluorescence and light scattering becomes important. (ddw-online.com)
  • The use of fluorescence lifetime (FLT) as the readout parameter for in vitro assays increases biochemical assay robustness against artefacts such as well-to-well volume variations, turbidity by precipitating particles and compound-related interferences. (ddw-online.com)
  • Enzyme activity assays, whereby the fluorescence lifetime of a reporter-labelled peptide substrate is directly affected by enzyme modification, have been successfully introduced for routine inhibitor profiling in automated processes within the hit-to-lead and lead optimisation phases for enzyme classes such as proteases, kinases and phosphatases3-7. (ddw-online.com)
  • In drug screening applications fluorescence artefacts and compound interference typically have fluorescence lifetimes of less than 5ns. (ddw-online.com)
  • However, many fluorophores currently used in assay applications have short fluorescence lifetimes in the range 1-5ns, and while these have been used in fluorescence lifetime applications they do not exploit the true potential of the technology. (ddw-online.com)
  • inhibitory
  • The effects of valproic acid (VPA), an antiepileptic drug with histone deacetylase inhibitory activity, on mononuclear cells isolated from 40 CLL patients were evaluated. (uliege.be)
  • Some tumors can evade detection by the immune system by exploiting inhibitory checkpoint pathways that suppress antitumor T-cell responses ( 1 ). (aacrjournals.org)
  • novel
  • To address this problem, a novel triblock copolymer has been developed to encapsulate several different hydrophobic drugs into stable polymer micelles. (hindawi.com)
  • We have recently developed a series of novel linear dendritic block copolymers (telodendrimers) comprising polyethylene glycol (PEG) and dendritic cholic acids (CA), which can encapsulate high concentrations of hydrophobic drugs such as paclitaxel and self-assemble to form stable core-shell micelles under aqueous condition ( 6-12 ). (aacrjournals.org)
  • It is highly desirable to discover novel tubulin ligands that could avoid or minimize these problems. (aacrjournals.org)
  • nanoparticles
  • Micellar nanoparticles based on linear polyethylene glycol (PEG) block dendritic cholic acids (CA) copolymers (telodendrimers), for the targeted delivery of chemotherapeutic drugs in the treatment of cancers, are reported. (aacrjournals.org)
  • The representative PEG 5k -CA 8 micellar nanoparticles possess the ideal properties for drug delivery, including high drug loading capacity, optimal particle size (20-60 nm), outstanding stability (more than 6 months at 4ºC), and sustainable drug release profile. (aacrjournals.org)
  • reported the influence of ligand and solvent effects on the size and shape of platinum nanoparticles. (wikipedia.org)
  • Hexadecylamine (HDA) was added to the purified reaction mixture and allowed to displace the THF and CO ligands over the course of approximately seven days, producing monodispersed spherical crystalline Pt nanoparticles with an average diameter of 2.1 nm. (wikipedia.org)
  • When the same procedure was followed using a stronger capping agent such as triphenyl phosphine or octanethiol, the nanoparticles remained spherical, suggesting that the HDA ligand affects particle shape. (wikipedia.org)
  • Research showed that alkylamine can coordinate with Pt2+ ion and form tetrakis(amine)platinate precursor and replace the original acac− ligand in Pt(acac)2, and oleic acid can further exchange with acac− and tune the formation kinetics of platinum nanoparticles. (wikipedia.org)
  • cytotoxic drug
  • Often, a large percentage of cytotoxic drug administered to the patient does not reach the tumor environment but rather is distributed throughout the body, resulting in the many toxic effects associated with chemotherapy and a narrowing of the drug's therapeutic window. (hindawi.com)
  • The mode of cytotoxic drug action was determined by annexin binding, DNA fragmentation, and caspase activation. (uliege.be)
  • therapeutics
  • The EPR effect is a consequence of the disorganized nature of the tumor vasculature, which results in increased permeability of polymer therapeutics and drug retention at the tumor site. (hindawi.com)
  • These results build confidence that any testing laboratory with access to one of these high-quality tests will be able to provide information relevant to clinical decision making with anti-PD-1 and anti-PD-L1 therapeutics, provided the correct assay cutoff is used. (aacrjournals.org)
  • Taxol
  • Agents acting at the process, such as Vinca alkaloids and Taxol analogues, have been used as first-line drugs for cancer patients. (aacrjournals.org)
  • The representative drugs in clinic of such mode of action are Vinca alkaloids (such as vincristine) that inhibit microtubule assembly and Taxol analogues (such as paclitaxel) that disrupt the microtubules disassembly ( 10 - 12 ). (aacrjournals.org)
  • activity
  • Nuclease activity via self-activation and anticancer activity of mononuclear copper (II) complex: Role of tertiary butyl group in the ligand frame, Manuscript under revision in Inorganic Chemistry 2012 , 51, 3343-45. (uta.edu)
  • In addition, false positive hits can easily be "weeded out" in this assay due to their activity in cells lacking caspase-8-inducible activity. (jove.com)
  • Immunotherapies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) demonstrate encouraging antitumor activity and manageable tolerability in non-small cell lung cancer (NSCLC), especially in patients with high tumor PD-L1 expression, as detected by companion or complementary diagnostic assays developed for individual agents. (aacrjournals.org)
  • There are two common strategies that are adopted for this type of experiment: Increasing the amount of radioligand added while maintaining both the constant specific activity and constant concentration of radioligand, or decreasing the specific activity of the radioligand due to the addition of an unlabeled ligand. (wikipedia.org)
  • Ligand specific recruitment of coregulators might be crucial for the agonist or antagonist activity of AR ligands. (wikipedia.org)
  • reliability
  • We have also found the Casp3 assay to be superior to analysis of apoptotic cells by the whole-mount TUNEL assay in regard to cost and reliability. (jove.com)
  • Essential aspects of binding assays include, but are not limited to, the concentration level of reactants or products (see radioactive section), maintaining the equilibrium constant of reactants throughout the assay, and the reliability and validity of linked reactions. (wikipedia.org)
  • chemotherapeutic agents
  • While some drugs and radioimaging agents are delivered to cells as folate conjugates in a one-to-one folate-to-conjugate ratio, folate-targeted liposomes allow for the delivery of larger amounts of chemotherapeutic agents. (wikipedia.org)
  • Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a category of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. (wikipedia.org)
  • immune
  • Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity). (wikipedia.org)
  • inhibitors
  • The fact that malignant cells are more susceptible to some proteasome inhibitors has been well recognized and a number of such drugs are currently in clinical trials. (aacrjournals.org)
  • mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). (wikipedia.org)
  • 20 crystal structures with and without ligands have been published and in 2010 nearly a dozen small molecule c-Met inhibitors have been tested clinically. (wikipedia.org)
  • mechanistic
  • From a mechanistic perspective, the FR functions to concentrate exogenous ligands (e.g. folates and folate-drug conjugates) into the cell cytosol by endocytosis. (wikipedia.org)
  • bone
  • Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow, digestive tract and hair follicles. (wikipedia.org)
  • potentially
  • Some have utilized the approach of chemically conjugating the active drug to a polymer to potentially improve stability. (hindawi.com)
  • This study builds optimism that harmonization between assays may be possible, and that the three assays studied could potentially be used interchangeably to identify patients most likely to respond to anti-PD-1/PD-L1 immunotherapies, provided the appropriate clinically defined algorithm and agent are always linked. (aacrjournals.org)
  • treatment
  • Recent Food and Drug Administration approval of the proteasome inhibitor bortezomib (PS-341) for treatment of relapsed and refractory multiple myeloma provides proof of principle that the proteasome is a valid target for anticancer therapy. (aacrjournals.org)
  • Furthermore, commercially available diagnostic assays are not standardized, and different assay methods could lead to inappropriate treatment selection. (aacrjournals.org)
  • As such, reliable testing assays are required to inform treatment choices. (aacrjournals.org)
  • Such advances provide researchers with the ability not only to quantify hormones and hormone receptors, but also to contribute important pharmacological information in drug development and treatment plans. (wikipedia.org)
  • In 1989 the United States Food and Drug Administration (FDA) approved it for use the treatment of prostate cancer. (wikipedia.org)
  • Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. (wikipedia.org)
  • Crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). (wikipedia.org)
  • competitive
  • Through the development of RIA technology, researchers have been able to move beyond the use of radioactivity, and instead, use liquid- and solid-phase, competitive, and immunoradiometric assays. (wikipedia.org)
  • Activator
  • Objective: Signal transducer and activator of transcription 3 (STAT3) is as a potential drug target for cancer and inflammation. (omicsonline.org)
  • chemotherapy
  • These prototype trials will be extremely informative in determining the role of the telomerase/telomere pathway in clinical oncology and, moreover, whether drugs targeting the unlimited replicative potential of cancer will find a place in cancer chemotherapy. (aacrjournals.org)
  • Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim to prolong life or to reduce symptoms (palliative chemotherapy). (wikipedia.org)
  • Combined modality chemotherapy is the use of drugs with other cancer treatments, such as surgery, radiation therapy, or hyperthermia therapy. (wikipedia.org)
  • Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used. (wikipedia.org)
  • Combination chemotherapy involves treating a patient with a number of different drugs simultaneously. (wikipedia.org)
  • development
  • This article charts FLT development to be a highly attractive tool for drug discovery. (ddw-online.com)
  • Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development prior to clinical trials. (wikipedia.org)
  • target
  • Target identification is the first step in developing new antimalarial drugs. (fiocruz.br)
  • It is based on the EADock DSS engine and also has scripts set up for curating common problems and preparing both the target protein and the ligand input files (Grosdidier et al. (fiocruz.br)
  • In the 1990s there was a dramatic change in this field due to studies on the mechanism of action of rapamycin and the identification of the drug target. (wikipedia.org)
  • cells
  • We have illustrated the molecule mode of action of this compound and the mechanism of why IG-105 is active against drug-resistant cancer cells. (aacrjournals.org)
  • Compared to acridine orange staining, which can identify apoptotic cells in live embryos in a matter of hours, Casp3 and TUNEL assays take considerably longer to complete (2-4 days). (jove.com)
  • different
  • Our study demonstrates analytic equivalence of tumor membrane staining between three different validated, commercially available PD-L1 IHC diagnostic assays. (aacrjournals.org)
  • agents
  • Additional translational approaches, such as targeting telomeres using G-quadruplex ligands, should result in antitelomere agents, such as RHPS4, entering the clinic in the near future. (aacrjournals.org)
  • Optimization of chemotherapeutic drug delivery is among the critical approaches to improve the therapeutic index of cytotoxic agents. (aacrjournals.org)
  • large
  • Modern drug discovery is thus usually a capital-intensive process that involves large investments by pharmaceutical industry corporations as well as national governments (who provide grants and loan guarantees). (wikipedia.org)
  • Meanwhile, for disorders whose rarity means that no large commercial success or public health effect can be expected, the orphan drug funding process ensures that people who experience those disorders can have some hope of pharmacotherapeutic advances. (wikipedia.org)
  • discovery
  • Drug discovery is done by pharmaceutical companies, with research assistance from universities. (wikipedia.org)
  • The "final product" of drug discovery is a patent on the potential drug. (wikipedia.org)
  • Screening of chemical libraries for AR blockers led to the discovery of the first antiandrogen, cyproterone. (wikipedia.org)
  • The discovery of vitamin-mediated drug targeting in plants led to the hypothesis that folate-targeted therapies could be of clinical use. (wikipedia.org)
  • Methods
  • Stained slides were read in batches on an assay-by-assay basis by a single pathologist trained in all methods, in a Clinical Laboratory Improvements Amendments program-certified laboratory. (aacrjournals.org)
  • cell
  • Afterwards, the empty FR returns to the cell surface where it can participate in another round of ligand-mediated endocytosis. (wikipedia.org)
  • high
  • The three assays showed similar patterns of tumor membrane staining, with high correlation between percent PD-L1 staining. (aacrjournals.org)
  • This makes the readout superior to other optical readout formats and capable of providing high quality primary screening data1. (ddw-online.com)
  • In addition, while providing high data quality, FLT-based assays are homogenous and scalable, and therefore compatible with medium- and high-throughput experiments. (ddw-online.com)