Abstract：
:Recombinant interferon-alpha (IFN) enhances the cytotoxic effects of the fluorinated pyrimidine, 5-fluorouracil (5FU), against two human colon cancer cell lines. The aspartate transcarbamylase (ATCase) inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), was studied in combination with 5FU/IFN to determine whether further anti-pyrimidine effects would result in greater cytotoxicity. By median effects analysis PALA synergistically augmented the cytotoxic effects of 5FU/IFN against both human colon cancer cell lines. This occurred in the absence of any effects of 5FU/IFN on ATCase and without further potentiation of the PALA-mediated inhibition of ATCase. To explore the mechanism by which this interaction occurred, detailed studies of pools of dNTPs were performed. Both 5FU/IFN and PALA/5FU/IFN treatments resulted in early (2-8 hr) depletion of pools of dTTP, but no effects on pools of dCTP. PALA had no effect on dTTP pools either alone or in the combination. In contrast, both PALA and PALA/5FU/IFN treatments resulted in later (12-24 hr) depletion of pools of dCTP. 5FU/IFN treatment had no effect on these pools. When pools of dCTP and dTTP were repleted by treatment with cytidine or thymidine, 20 microM, however, there was only partial reversal of cytotoxicity induced by 5FU/IFN + PALA, suggesting that the synergy observed did not result solely from a sequential anti-pyrimidine effect. The incorporation of 5FU into RNA was also studied; PALA enhanced the incorporation of [6-3H]5FU into RNA by 83-150%, but not into DNA, suggesting an alternative mechanism of drug interaction.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Wadler S,Mao X,Bajaj R,Hallam S,Schwartz ELsubject
Has Abstractpub_date
1993-11-01 00:00:00pages
1070-6issue
5eissn
0026-895Xissn
1521-0111journal_volume
44pub_type
杂志文章abstract：:Cultured murine hepatoma 1c1c7 cells were treated with either the actin filament-disrupting drug cytochalasin D or the microtubule inhibitors colchicine and nocadazole (NOC) to assess the role of the cytoskeleton in the process of cytochrome P450 Cyp1a-1 induction. Indirect fluorescence analyses demonstrated that micr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-05-01 00:00:00
abstract：:Recently, inositol hexakisphosphate (phytic acid) was shown to bind to photoreceptor arrestin and block its interaction with rhodopsin. Such an interaction might predict that inositol polyphosphates could alter G protein-coupled receptor desensitization. To investigate the possible roles of higher inositol polyphospha...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-08-01 00:00:00
abstract：:The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-12-01 00:00:00
abstract：:Metallothioneins (MTs) are cytoplasmic proteins that sequester certain divalent cations and are considered a primary cellular defense against the toxic transition metal cadmium (Cd(2+)). MT-I/II(-/-) knockout [MT(-/-)] cells are available and serve as an excellent tool to study non-MT-related mechanisms in metal toler...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.014241
更新日期：2006-02-01 00:00:00
abstract：:Prolonged ethanol exposure causes central nervous system hyperexcitability that involves a loss of GABAergic inhibition. We previously demonstrated that long-term ethanol exposure enhances the internalization of synaptic GABA(A) receptors composed of alpha1beta2/3gamma2 subunits. However, the mechanisms of ethanol-med...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.063016
更新日期：2010-05-01 00:00:00
abstract：:The ability of four antidepressant drugs, imipramine, alaproclate, norzimelidine, and fluvoxamine, to inhibit serotonin transport into platelet plasma membrane vesicles was tested over a range of external Na+ concentrations. Imipramine affinity, as we previously reported [J. Biol. Chem. 258:6115-6119 (1983)] increases...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-06-01 00:00:00
abstract：:G-protein-coupled receptor activation is generally analyzed under equilibrium conditions. However, real-life receptor functions are often dependent on very short, transient stimuli that may not allow the achievement of a steady state. This is particularly true for synaptic receptors such as the α(2A)-adrenergic recept...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.077693
更新日期：2012-06-01 00:00:00
abstract：:Pertussis toxin (PTX) ADP-ribosylates alpha subunits of GTP-binding proteins (G proteins) when they are in association with beta gamma dimers, and free alpha subunits are thought not to be substrates under standard assay conditions. We now report the rather unexpected discovery that synthetic peptides encompassing the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-11-01 00:00:00
abstract：:We demonstrated previously that the nucleoside of fludarabine (F-ara-A), a clinically effective agent against chronic lymphocytic leukemia and low-grade lymphoma, produces synergistic cytotoxicity against cisplatin-resistant CP2.0 human colon tumor cells when administered in combination with cisplatin. The purpose of ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.5.798
更新日期：1997-11-01 00:00:00
abstract：:Past decades of cancer research have mainly focused on the role of various extracellular and intracellular biochemical signals on cancer progression and metastasis. Recent studies suggest an important role of mechanical forces in regulating cellular behaviors. This review first provides an overview of the mechanobiolo...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.116.106765
更新日期：2016-12-01 00:00:00
abstract：:The immunosuppressive agent cyclosporine A has been shown to reverse multidrug resistance (MDR) in malignant cells. In the present study, a 3H-cyclosporine diazirine analogue was used to photolabel viable MDR Chinese hamster ovary cells. The 170-kDa membrane P-glycoprotein, which functions as a drug efflux pump, was s...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-10-01 00:00:00
abstract：:The nucleoside analogue, 3-deazaadenosine (c3-Ado), serves both as a substrate and as an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, and the ability of this compound to induce accumulation of intracellular AdoHcy and S-3-deazaadenosylhomocysteine (c3-AdoHcy) in various cells and species has been widely doc...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-08-01 00:00:00
abstract：:Diltiazem is a widely prescribed Ca2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral CaV channel construct CaVAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca2+ channel underneath ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.117531
更新日期：2019-10-01 00:00:00
abstract：:At sites of inflammation, endothelial cells play a major role in defining the types of leukocytes that are recruited to a specific area. This is accomplished, at least in part, through the cytokine induction of cell surface adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1). We investigated the r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-06-01 00:00:00
abstract：:The activities of phosphorylase kinase and myosin light-chain kinase are regulated by Ca2+ binding to calmodulin. However, differences in the activation properties of the purified enzymes are apparent, since calmodulin binds to phosphorylase kinase in the absence of Ca2+ whereas prior formation of a Ca2+ . calmodulin ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:Understanding the structures of active and inactive agonist- and antagonist-bound receptor complexes is of great interest. In this work, we focus on position 30 of cholecystokinin (CCK) and its spatial approximation with the type A CCK receptor. For this, we developed two photoaffinity labeling probes, replacing the n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.012179
更新日期：2005-06-01 00:00:00
abstract：:A polyamine component of Agelenopsis aperta spider venom designated FTX is reported to be a selective antagonist of P-type calcium channels in the mammalian brain. Consequently, this component has frequently been used as a pharmacological tool to determine the presence, distribution, and function of P-type channels in...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-10-01 00:00:00
abstract：:Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term pote...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.082891
更新日期：2013-04-01 00:00:00
abstract：:The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na(+) channel, which includes an in-frame deletion of three amino a...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-02-01 00:00:00
abstract：:Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) by N(5),N(10)-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.115.099614
更新日期：2015-12-01 00:00:00
abstract：:Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensive...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.068007
更新日期：2010-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.119.119321
更新日期：2020-10-01 00:00:00
abstract：:The epipodophyllotoxin etoposide is an inhibitor of topoisomerase II. The effects of this agent on gene expression, particularly the transcriptional induction of genes implicated in growth control, are unknown. The present results demonstrate that etoposide induces expression of the c-jun protooncogene in HL-60 myeloi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-06-01 00:00:00
abstract：:The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nit...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.053124
更新日期：2009-06-01 00:00:00
abstract：:Vesnarinone, a cardiotonic agent, blocks I(Kr) and, unlike other I(Kr) blockers, produces a frequency-dependent prolongation of action potential duration (APD). To elucidate the mechanisms, we studied the effects of vesnarinone on HERG, the cloned human I(Kr) channel, heterologously expressed in Xenopus laevis oocytes...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.60.2.244
更新日期：2001-08-01 00:00:00
abstract：:The gamma-aminobutyric acid (GABA) receptor type B (GABA(B)R) is constituted of at least two homologous proteins, GABA(B)R1 and GABA(B)R2. These proteins share sequence and structural similarity with metabotropic glutamate and Ca(2+)-sensing receptors, both of which are sensitive to Ca(2+). Using rat brain membranes, ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.57.3.419
更新日期：2000-03-01 00:00:00
abstract：:In rat pancreatic zymogen granules (ZG), an ATP-sensitive K(+) conductance and a Cl(-) conductance have been characterized that are inversely regulated by an approximately 65-kDa multidrug resistance P-glycoprotein (mdr1) gene product. In search of a label for purification of this protein, we found that the dihydropyr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-02-01 00:00:00
abstract：:Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the alpha1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the alpha1 subunit. We generated concatemers of subunits so that the alpha...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.053629
更新日期：2009-04-01 00:00:00
abstract：:Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.001313
更新日期：2004-09-01 00:00:00
abstract：:To understand the molecular mechanism by which the angiotensin II (AII) type 1 receptor (AT1 receptor) transduces its biological signal, we examined the role of various signaling molecules involved in AT1 receptor signaling in Chinese hamster ovary cells stably transfected with the AT1 receptor. AT1 receptor-transfect...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-09-01 00:00:00
