Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphocyte chromatin lability to acid hyrolysis was studied using acridine orange fluorescence metachromasia in a high-lymphocytic-leukemia-susceptibility strain (AKR) and random-bred mice (ICR). Comparisons were made of blood, thymus, and spleen lymphocytes between random-bred, "normal" AKR, and leukemic AKR animals. The leukemic mice were in the stages of the disease characterized by enlarged thymus and spleen but preceding massive elevation of blood lymphocytes. The ranges of the mean chromatin acid lability overlapped and were nearly identical in peripheral blood lymphocytes. However, thymic and splenic lymphocytes showed a marked rise in mean chromatic acid lability in the leukemic animals. The ranges of the mean values of this parameter were also found to be far greater in the lymphopoietic organs of normal AKR than in the random-bred mice. The data indicate that anatomically normal AKR animals of an age in which they are highly susceptible to spontaneous lymphocytic leukemia may contain a greater number of lymphoblasts in both the spleen and the thymus than do comparable random-bred mice. The implications of these findings are discussed in relation to strain differences and the concept of thymic origin of lymphocytic leukemia in mice.
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PMID:Microfluorometry of nuclear acridine orange metachromasia in lymphocytes of thymus, spleen, and blood of AKR and random-bred mice. 5 32

Simultaneous staining of deoxyribonucleic (DNA) and ribonucleic acid (RNA) in nonfixed, but permeable, cells is described. Cells are made permeable by treatment with non-ionic detergent at low pH. RNA is denatured prior to, or during staining, by exposure of cells to chelating agents to ensure that DNA (native) and RNA (dentured) may be stained differentially with the metachromatic dye, acridine orange. The fluorescence of individual cells is measured in a flow cytofluorometer. A comparison between various staining procedures employing acridine orange or other intercalating dyes in unfixed cells is discussed in terms of staining specificity, cell permeability and preservation. Evidence is provided that acridine orange staining of unfixed cells may be used as a simple, fast means of obtaining information on cell ploidy levels and cell cycle status from DNA measurements (green fluorescence), and cell transcriptional activity from RNA staining (red fluorescence), in human and murine cells lines, peripheral blood and bone marrow specimens from patients with leukemia and mitogenically (phytohemagglutinin) or antigenically (mixed lymphocyte culture) stimulated human peripheral blood cultures. Exposure of cells to detergent at low pH as an alternative to cell fixation or hypotonic treatment is proposed as a fast, convenient method of making cells permeable to dyes.
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PMID:Simultaneous staining of ribonucleic and deoxyribonucleic acids in unfixed cells using acridine orange in a flow cytofluorometric system. 6 67

Sublines of P388 leukemia resistant to Adriamycin and daunorubicin were cross-resistant to actinomycin D in vivo and in vitro. The Adriamycin-resistant cell line was 1000-fold resistant to actinomycin D on 1-hr exposure in vitro and 370-fold resistant when exposed to the drug for 16 hr. The immediate binding of radioactive actinomycin D to sensitive and resistant cells was similar, and the uptake of the drug by the resistant cells was only about 27% less than the rate of uptake by sensitive cells. There was a dramatic difference in efflux of drug from sensitive and resistant sublines. Equivalent cytotoxicity of actinomycin D for the sensitive and resistant sublines was obtained at concentrations of the drug that resulted in approximately equivalent levels of net retention of actinomycin D (retained drug minus background levels of immediate binding of the drug to the cells). Incubation of cells in the presence of actinomycin D plus either Tween 80 or acridine orange incresed the rate of uptake and the percentage of actinomycin D retained by the resistant cells on short-term assays but did not reverse the resistance. It is concluded that these tumors must retain appreciable concentrations of actinomycin D for several hr in order to be killed. The anthracycline-resistant sublines are cross-resistant to actinomycin D by virtue of their inability to retain the drug.
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PMID:Decreased retention of actinomycin D as the basis for cross-resistance in anthracycline-resistant sublines of P388 leukemia. 92 43

A series of substituted dibenzo[1,4]dioxin-1-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[1,4]dioxin-1-carboxylic acids were prepared by a variety of methods. No regiospecific syntheses were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[1,4]dioxin-1-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structure-activity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo[1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase II alpha. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the topo II beta isozyme.
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PMID:Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents. 131 Jan 19

A hybrid molecule, which combines an anilinoacridine chromophore related to the antitumour drug amsacrine (m-AMSA) and a bispyrrole moiety analogous to the antiviral agent netropsin, has been examined for its ability to bind chromatin and to modulate the activity of topoisomerase II. The results show that the presence of histones does not alter the bimodal DNA binding process. Intercalation of the acridine and groove binding of the netropsin part of the drug are both observed with chromatin preparations. Moreover, the hybrid has a clear topoisomerase II-DNA cleavable complex-inducing activity close to that of m-AMSA. The role of the two parts of the hybrid ligand is discussed in relation to ternary complex formation. Two cell lines (L1210 leukemia and MCF7 mammary carcinoma) were compared in their sensitivity to the tested ligand. The drug, which appears to be an efficient growth inhibitor of leukemic cells in vitro, reveals moderate activity against P388 leukemia in vivo. The biological activity of the hybrid may derive from a mechanism that involves DNA binding and topoisomerase II inhibition. This study demonstrates that agents which intercalate and bind to the minor groove of DNA simultaneously represent a new class of drugs interfering with topoisomerase II and provide opportunities for the development of new antitumour agents.
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PMID:Biological activity and molecular interaction of a netropsin-acridine hybrid ligand with chromatin and topoisomerase II. 131 80

Anthracycline accumulation was evaluated by flow cytometry or radiolabeled drug assays in cells and cytoplasts (enucleated cells) prepared from parental and multidrug-resistant human K562 leukemia cells. Treatment with energy inhibitors, such as dinitrophenol (DNP) or sodium azide/deoxyglucose, led to a marked decrease in daunorubicin accumulation in parental cells and cytoplasts. Another ionophore, monensin, also caused a significant decrease in daunorubicin accumulation; however, ATPase inhibitors ouabain, vanadate, and N-ethylamaleimide had little or no effect. The lysosomatropic agents chloroquine and methylamine caused a moderate decrease in anthracycline accumulation. Fluorescence microscopy showed that the DNP-sensitive daunorubicin uptake occurred in a nonnuclear subcellular compartment. Studies using increasing daunorubicin concentrations demonstrated fluorescence quenching that occurred in the nonnuclear, DNP-sensitive compartment. The effect of inhibitors on the accumulation of rhodamine 123 and acridine orange strongly implicated lysosomes as the principal compartment of this inhibitable daunorubicin accumulation. Cytoplasts from P-glycoprotein containing multidrug-resistant K562 cells demonstrated a verapamil-reversible, decreased daunorubicin accumulation that was observed in resistant whole cells. Verapamil pretreatment of cytoplasts from resistant cells revealed the subcellular DNP-sensitive uptake present in parental cytoplasts. These studies demonstrate that cytoplasts are an effective means to study drug transport in mammalian cells without nuclear drug binding. Parental K562 cells and cytoplasts exhibit an energy-dependent accumulation of daunorubicin into cytoplasmic organelles that is also present in resistant cells and cytoplasts when P-glycoprotein mediated efflux is inhibited.
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PMID:Energy-dependent accumulation of daunorubicin into subcellular compartments of human leukemia cells and cytoplasts. 135 Feb 80

Cell kinetic differences have been described between acute lymphoblastic leukemia with L1 and L2 morphology. We now report cytokinetic and DNA ploidy findings of the rare L3 B-cell leukemia/lymphoma. Flow cytometry analysis of nineteen samples was performed by simultaneous DNA-RNA staining with acridine orange. RNA and DNA indices and cell cycle distributions were calculated. The RNA-index of the G0/G1 cells was 17.9 +/- 8.7 and the number of cells in S phase and S + G2M were 21 +/- 10.6 and 28.0 +/- 13.9 percent respectively. DNA aneuploidy was found in 6/19 (31.6%) and in two cases multiple aneuploid cell lines were observed. DNA aneuploidy and multiple abnormal stemlines adversely affected survival (p less than 0.05), while kinetic parameters did not affect survival (p greater than 0.05). The cytokinetic data are significantly different (S phase and RNA-I; p less than 0.001) than previously reported for the L1 and L2 ALL. Abnormal DNA stemlines were found in cases with no detected cytogenetic abnormalities. This study confirms that L3 ALL is characterized by significantly increased proliferation and provides a means for a flow cytometric identification of this subtype as compared to L1 and L2 ALL.
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PMID:Flow cytometric analysis of cytokinetics of L3-acute lymphoblastic leukemia/lymphoma. 140 16

A series of some N-alkylaminoalkyl derivatives of pyrimido[5,6,1-d,e]acridine-1,3,7-trione (3) was synthesized as new potential antitumor drugs, starting from the suitable 9,10-dihydro-9-oxo-4-acridinecarboxamides and using phosgene as cyclizing agent. 1-(9,10-dihydro-9-oxo-4-acridinecarbonyl)-3-alkyl-2-imidazolido nes were also obtained as side products. The final products 3 and some carboxamides were tested "in vitro" against L 1210 leukemia and "in vivo" against P388 leukemia. Of the tested compounds, one is active "in vivo", another shows significant cytotoxic activity "in vitro", but is inactive or toxic "in vivo".
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PMID:Pyrimidoacridine derivatives as potential antitumor agents. 144 11

A series of acridine-2- and -4-carboxamide-linked analogues of PtenCl2 has been prepared and evaluated for biological activity against several tumor cell lines in vitro and in vivo. The platinum complexes were generally more cytotoxic than the corresponding ligands against wild-type P388 leukemia cells in vitro, with acridine-4-carboxamide complexes being the more effective. In contrast to cisplatin and PtenCl2, the complexes were equally active in vitro against both wild-type and cisplatin-resistant P388 lines. The 4-carboxamide complexes showed high levels of in vivo activity (ILS greater than 100%) against wild-type P388 using a single-dose protocol, and one compound was also significantly active in vivo in a cisplatin-resistant line, against which cisplatin and PtenCl2 are inactive.
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PMID:DNA-directed alkylating agents. 5. Acridinecarboxamide derivatives of (1,2-diaminoethane)dichloroplatinum(II). 150 Dec 23

The synthesis of two peptidic derivatives, including an anilinoacridine chromophore (related to the antileukemic drug amsacrine) and either the tetrapeptide SPKK (a nucleic acid-binding unit) (1) or the octapeptide SPKKSPKK (2), has been carried out. The interaction of both drugs with DNA has been studied. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the tetrapeptidic or octapeptidic portion is located in the DNA minor groove. Compound 1 fully intercalates into DNA. In contrast, minor groove binding of the octapeptide SPKKSPKK seems to partially modify the intercalative properties of the acridine moiety of 2. In vitro cytostatic and cytotoxic activities against a murine leukemia cell line (L1210), as well as inhibition of [3H]thymidine incorporation, are reported. Compound 1, which is a better inhibitor of DNA synthesis than 2, is also 2.8-fold more potent in terms of growth inhibition. Both drugs are efficient cytostatic agents, but are weakly cytotoxic. The DNA-binding abilities of the two molecules are well correlated to their biological properties. Thus, DNA can be considered as the primary target for these new ligands.
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PMID:Relationship between DNA-binding and biological activity of anilinoacridine derivatives containing the nucleic acid-binding unit SPKK. 154 29


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