P-Glycoprotein: A 170-kDa transmembrane glycoprotein from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many ANTINEOPLASTIC AGENTS. Overexpression of this glycoprotein is associated with multidrug resistance (see DRUG RESISTANCE, MULTIPLE).Drug Resistance, Multiple: Simultaneous resistance to several structurally and functionally distinct drugs.P-Glycoproteins: A subfamily of transmembrane proteins from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS that are closely related in sequence to P-GLYCOPROTEIN. When overexpressed, they function as ATP-dependent efflux pumps able to extrude lipophilic drugs, especially ANTINEOPLASTIC AGENTS, from cells causing multidrug resistance (DRUG RESISTANCE, MULTIPLE). Although P-Glycoproteins share functional similarities to MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS they are two distinct subclasses of ATP-BINDING CASSETTE TRANSPORTERS, and have little sequence homology.Rhodamine 123: A fluorescent probe with low toxicity which is a potent substrate for P-glycoprotein and the bacterial multidrug efflux transporter. It is used to assess mitochondrial bioenergetics in living cells and to measure the efflux activity of P-glycoprotein in both normal and malignant cells. (Leukemia 1997;11(7):1124-30)Verapamil: A calcium channel blocker that is a class IV anti-arrhythmia agent.Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.Genes, MDR: Genes for MEMBRANE TRANSPORT PROTEINS that confer resistance to toxic compounds. Several superfamilies of these multidrug export proteins are known and found in both prokaryotes and eukaryotes.Daunorubicin: A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS.Vinblastine: Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)ATP-Binding Cassette Transporters: A family of MEMBRANE TRANSPORT PROTEINS that require ATP hydrolysis for the transport of substrates across membranes. The protein family derives its name from the ATP-binding domain found on the protein.Multidrug Resistance-Associated Proteins: A sequence-related subfamily of ATP-BINDING CASSETTE TRANSPORTERS that actively transport organic substrates. Although considered organic anion transporters, a subset of proteins in this family have also been shown to convey drug resistance to neutral organic drugs. Their cellular function may have clinical significance for CHEMOTHERAPY in that they transport a variety of ANTINEOPLASTIC AGENTS. Overexpression of proteins in this class by NEOPLASMS is considered a possible mechanism in the development of multidrug resistance (DRUG RESISTANCE, MULTIPLE). Although similar in function to P-GLYCOPROTEINS, the proteins in this class share little sequence homology to the p-glycoprotein family of proteins.Blood-Brain Barrier: Specialized non-fenestrated tightly-joined ENDOTHELIAL CELLS with TIGHT JUNCTIONS that form a transport barrier for certain substances between the cerebral capillaries and the BRAIN tissue.AcridinesCyclosporins: A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection.Tetrahydroisoquinolines: A group of ISOQUINOLINES in which the nitrogen containing ring is protonated. They derive from the non-enzymatic Pictet-Spengler condensation of CATECHOLAMINES with ALDEHYDES.Biological Transport: The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Loperamide: One of the long-acting synthetic ANTIDIARRHEALS; it is not significantly absorbed from the gut, and has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally.Drug Resistance, Neoplasm: Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.Digoxin: A cardiotonic glycoside obtained mainly from Digitalis lanata; it consists of three sugars and the aglycone DIGOXIGENIN. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in ATRIAL FIBRILLATION and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. (From Martindale, The Extra Pharmacopoeia, 30th ed, p666)LLC-PK1 Cells: Epithelial cell line originally derived from porcine kidneys. It is used for pharmacologic and metabolic studies.Azides: Organic or inorganic compounds that contain the -N3 group.Dibenzocycloheptenes: A family of tricyclic hydrocarbons whose members include many of the commonly used tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC).Cyclosporine: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).Caco-2 Cells: Human colonic ADENOCARCINOMA cells that are able to express differentiation features characteristic of mature intestinal cells, such as ENTEROCYTES. These cells are valuable in vitro tools for studies related to intestinal cell function and differentiation.KB Cells: This line KB is now known to be a subline of the ubiquitous KERATIN-forming tumor cell line HeLa. It was originally thought to be derived from an epidermal carcinoma of the mouth, but was subsequently found, based on isoenzyme analysis, HeLa marker chromosomes, and DNA fingerprinting, to have been established via contamination by HELA CELLS. The cells are positive for keratin by immunoperoxidase staining. KB cells have been reported to contain human papillomavirus18 (HPV-18) sequences.Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells.Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. Its primary therapeutic use is in the treatment of gout, but it has been used also in the therapy of familial Mediterranean fever (PERIODIC DISEASE).Rhodamines: A family of 3,6-di(substituted-amino)-9-benzoate derivatives of xanthene that are used as dyes and as indicators for various metals; also used as fluorescent tracers in histochemistry.Dihydropyridines: Pyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position.QuinolinesCytochrome P-450 CYP3A: A cytochrome P-450 suptype that has specificity for a broad variety of lipophilic compounds, including STEROIDS; FATTY ACIDS; and XENOBIOTICS. This enzyme has clinical significance due to its ability to metabolize a diverse array of clinically important drugs such as CYCLOSPORINE; VERAPAMIL; and MIDAZOLAM. This enzyme also catalyzes the N-demethylation of ERYTHROMYCIN.Adenosine Triphosphatases: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Antibiotics, Antineoplastic: Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.Quinidine: An optical isomer of quinine, extracted from the bark of the CHINCHONA tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular ACTION POTENTIALS, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Vault Ribonucleoprotein Particles: Large cytoplasmic ribonucleoprotein particles that have an eight-fold symmetry with a central pore and petal-like structure giving the appearance of an octagonal dome. (The Dictionary of Cell Biology, Lackie and Dow, 2nd ed.)Vincristine: An antitumor alkaloid isolated from VINCA ROSEA. (Merck, 11th ed.)Antineoplastic Agents, Phytogenic: Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity.Terfenadine: A selective histamine H1-receptor antagonist devoid of central nervous system depressant activity. The drug was used for ALLERGY but withdrawn due to causing LONG QT SYNDROME.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Affinity Labels: Analogs of those substrates or compounds which bind naturally at the active sites of proteins, enzymes, antibodies, steroids, or physiological receptors. These analogs form a stable covalent bond at the binding site, thereby acting as inhibitors of the proteins or steroids.Neoplasm Proteins: Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.Fluoresceins: A family of spiro(isobenzofuran-1(3H),9'-(9H)xanthen)-3-one derivatives. These are used as dyes, as indicators for various metals, and as fluorescent labels in immunoassays.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Biological Availability: The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.Adenosine Triphosphate: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Herb-Drug Interactions: The effect of herbs, other PLANTS, or PLANT EXTRACTS on the activity, metabolism, or toxicity of drugs.Flupenthixol: A thioxanthene neuroleptic that, unlike CHLORPROMAZINE, is claimed to have CNS-activating properties. It is used in the treatment of psychoses although not in excited or manic patients. (From Martindale, The Extra Pharmacopoeia, 30th ed, p595)Celastraceae: A plant family of the order Celastrales, subclass Rosidae, class Magnoliopsida.Paclitaxel: A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS BREVIFOLIA. It stabilizes MICROTUBULES in their polymerized form leading to cell death.Photoaffinity Labels: Biologically active molecules which are covalently bound to the enzymes or binding proteins normally acting on them. Binding occurs due to activation of the label by ultraviolet light. These labels are used primarily to identify binding sites on proteins.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Intestinal Absorption: Uptake of substances through the lining of the INTESTINES.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.Technetium Tc 99m Sestamibi: A technetium imaging agent used to reveal blood-starved cardiac tissue during a heart attack.Tissue Distribution: Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios.Area Under Curve: A statistical means of summarizing information from a series of measurements on one individual. It is frequently used in clinical pharmacology where the AUC from serum levels can be interpreted as the total uptake of whatever has been administered. As a plot of the concentration of a drug against time, after a single dose of medicine, producing a standard shape curve, it is a means of comparing the bioavailability of the same drug made by different companies. (From Winslade, Dictionary of Clinical Research, 1992)K562 Cells: An ERYTHROLEUKEMIA cell line derived from a CHRONIC MYELOID LEUKEMIA patient in BLAST CRISIS.Intestines: The section of the alimentary canal from the STOMACH to the ANAL CANAL. It includes the LARGE INTESTINE and SMALL INTESTINE.Fluorescent Dyes: Agents that emit light after excitation by light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags.Biological Transport, Active: The movement of materials across cell membranes and epithelial layers against an electrochemical gradient, requiring the expenditure of metabolic energy.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Vanadates: Oxyvanadium ions in various states of oxidation. They act primarily as ion transport inhibitors due to their inhibition of Na(+)-, K(+)-, and Ca(+)-ATPase transport systems. They also have insulin-like action, positive inotropic action on cardiac ventricular muscle, and other metabolic effects.Poloxalene: A copolymer of polyethylene and polypropylene ether glycol. It is a non-ionic polyol surface-active agent used medically as a fecal softener and in cattle for prevention of bloat.Oxidoreductases, N-DemethylatingCell Line, Tumor: A cell line derived from cultured tumor cells.Benzylisoquinolines: ISOQUINOLINES with a benzyl substituent.Saquinavir: An HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases, and also inhibits CYTOCHROME P-450 CYP3A.Hypericum: Genus of perennial plants in the family CLUSIACEAE (sometimes classified as Hypericaceae). Herbal and homeopathic preparations are used for depression, neuralgias, and a variety of other conditions. Hypericum contains flavonoids; GLYCOSIDES; mucilage, TANNINS; volatile oils (OILS, ESSENTIAL), hypericin and hyperforin.Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Central Nervous System Agents: A class of drugs producing both physiological and psychological effects through a variety of mechanisms. They can be divided into "specific" agents, e.g., affecting an identifiable molecular mechanism unique to target cells bearing receptors for that agent, and "nonspecific" agents, those producing effects on different target cells and acting by diverse molecular mechanisms. Those with nonspecific mechanisms are generally further classed according to whether they produce behavioral depression or stimulation. Those with specific mechanisms are classed by locus of action or specific therapeutic use. (From Gilman AG, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p252)Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Leukemia P388: An experimental lymphocytic leukemia originally induced in DBA/2 mice by painting with methylcholanthrene.Phloroglucinol: A trinitrobenzene derivative with antispasmodic properties that is used primarily as a laboratory reagent.Drug Screening Assays, Antitumor: Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.Kinetics: The rate dynamics in chemical or physical systems.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Capillaries: The minute vessels that connect the arterioles and venules.Mitoxantrone: An anthracenedione-derived antineoplastic agent.Inhibitory Concentration 50: The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.Madin Darby Canine Kidney Cells: An epithelial cell line derived from a kidney of a normal adult female dog.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.HIV Protease Inhibitors: Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Prazosin: A selective adrenergic alpha-1 antagonist used in the treatment of HEART FAILURE; HYPERTENSION; PHEOCHROMOCYTOMA; RAYNAUD DISEASE; PROSTATIC HYPERTROPHY; and URINARY RETENTION.Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Membrane Transport Modulators: Agents that affect ION PUMPS; ION CHANNELS; ABC TRANSPORTERS; and other MEMBRANE TRANSPORT PROTEINS.14-alpha Demethylase Inhibitors: Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Phenothiazines: Compounds containing dibenzo-1,4-thiazine. Some of them are neuroactive.Administration, Oral: The giving of drugs, chemicals, or other substances by mouth.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Bile Canaliculi: Minute intercellular channels that occur between liver cells and carry bile towards interlobar bile ducts. Also called bile capillaries.Ketoconazole: Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.
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