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)

C3H/He-mg and AKR mice were injected intraperitoneally with lymphocytes prepared from the spleen of (C3H/He-mg x AKR)F1 hybrid mice bearing Gross-virus leukemia. Lymphocyte suspensions were prepared from the spleen, mesenteric lymph node and thymus of mice at different days after the injection and analyzed for the ratio of leukemic to normal lymphocytes with a flow cytometer. The size and the fluorescein content of the cells incubated with fluorescein diacetate served for the distinction between normal and leukemic lymphocytes. After injection with leukemic lymphocytes, lethal leukemia developed in the AKR strain, whereas the C3H/He-mg strain was characterized by a spontaneous regression after a transient development of leukemia. The percentage of leukemic lymphocytes was the highest in the spleen and it was the lowest in the thymus regardless of the stage of the disease. In the thymus of C3H/he-mg mice the leukemic lymphocytes could be detected only during the crisis period.
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PMID:A follow-up study of the progression or spontaneous regression of leukemia in mouse strains. 695 43

Toxiusol, a natural product isolated from the Red Sea sponge Toxiclona toxius, has been shown to be a potent inhibitor of various viral reverse transcriptases (RT) [i.e., of human immunodeficiency virus (HIV-1), equine infectious anemia virus, and murine leukemia virus] and cellular DNA polymerases (i.e., of DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). A thorough investigation of the mode of inhibition was conducted with HIV-1 RT-associated DNA polymerase activity. The inhibition is unaffected by the nature of template-primer used. The inhibitory active site of toxiusol is attributable to the polar moieties at the benzene ring. The presence of either sulfate groups in the natural lead compound or hydroxyl groups in the corresponding hydroquinone is critical, because both compounds are equally effective at low micromolar concentrations. Conversely, the presence of acetyl groups in the same position in the derivative toxiusol diacetate lowers significantly or abolishes the inhibitory activity. Toxiusol binds the HIV-1 RT irreversibly and in a noncompetitive way with high affinity (Ki = 1.2 microM), probably through polar groups. The replacement with acetyl moieties in the analog toxiusol diacetate hampers the binding of the inhibitor to the enzyme (Ki increases to about 26 microM). Still, the compound binds irreversibly, probably through its hydrophobic structure skeleton. Toxiusol diacetate loses its ability to inhibit the first step in the DNA polymerization process (that is, the formation of the DNA-enzyme complex as measured by a gel retardation assay), which contributes to its poor inhibitory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of inhibition of HIV reverse transcriptase by toxiusol, a novel general inhibitor of retroviral and cellular DNA polymerases. 753 6

The semiautomated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) to fluorescein in microtiter plates, was used for in vitro evaluation of Cladribine (2-chlorodeoxyadenosine, CdA) interactions with five standard antileukemic drugs: amsacrine (Am), etoposide (VP16), daunorubicin (Dnr), cytosine arabinoside (AraC), and mitoxantrone (Mit). Samples from 31 patients with acute myelocytic leukemia (AML) were tested with continuous drug exposure. A large heterogeneity with respect to cell kill was observed for all combinations tested. An additive model provided a significantly better fit of the data compared to the effect of the most active single agent of the combination (Dmax) only for CdA+AraC. When the frequency of additive and synergistic interactions were calculated according to the multiplicative concept for drug interactions, the highest frequencies were observed for CdA+AraC and CdA+Dnr. This interaction pattern was confirmed by isobologram analysis. Cross-resistance analysis revealed high correlations between CdA and AraC whereas the correlations were weaker between CdA and the other drugs. The highest frequency of synergistic interactions was obtained for AraC+CdA, despite their cross-resistance. Of the non-cross-resistant drugs tested, Dnr appears to be the most effective adjunct to CdA in terms of interactions at the cellular level.
Leukemia 1994 Oct
PMID:Interactions between cladribine (2-chlorodeoxyadenosine) and standard antileukemic drugs in primary cultures of human tumor cells from patients with acute myelocytic leukemia. 793 68

The Kurloff cell (KC) of the guinea-pig develops natural killer cytotoxic activity in heterologous systems. We report in this paper the effective in vitro cytotoxic activity of the KC in a homologous guinea-pig system, i.e. against the guinea-pig target leukemic L2C cells. A dual-color flow analysis of homologous effector-target conjugates, using calcein-labeled KC and hydroethidine-labeled L2C shows a 40% frequency KC-L2C conjugation. The specific cytotoxicity of KC against L2C (78%) was estimated as the target-loss of green fluorescence due to hydrolysed carboxy-fluorescein diacetate after 4 hours at 37 degrees C. We propose that the Kurloff cell could be involved in surveillance against spontaneously arising leukemic cells, and this could be an explanation for the high degree of resistance to spontaneous or experimentally-induced cancers, in the guinea-pig.
Leukemia 1993 May
PMID:In vitro cytotoxic effect of guinea-pig natural killer cells (Kurloff cells) on homologous leukemic cells (L2C). 848 26

A series of 3- and 5-alkylamino derivatives, as well as other structurally modified analogues of pyridine-2-carboxaldehyde thiosemicarbazone, have been synthesized and evaluated as inhibitors of CDP reductase activity and for their cytotoxicity in vitro and antineoplastic activity in vivo against the L1210 leukemia. Alkylation of 3- and 5-amino-2-(1,3-dioxolan-2-yl)pyridines (1, 2) resulted in corresponding 3-methylamino, 5-methylamino, 3-allylamino, 5-ethylamino, 5-allylamino, 5-propylamino, and 5-butylamino derivatives (5, 6, and 11-15), which were then condensed with thiosemicarbazide to yield the respective thiosemicarbazones (7, 8, and 16-20). Oxidation of 3,5-dinitro-2-methylpyridine (21) with selenium dioxide, followed by treatment with ethylene glycol and p-toluenesulfonic acid, produced the cyclic ethylene acetal, 23. Oxidation of 2-(1,3-dioxolan-2-yl)-4-methyl-5-nitropyridine (26) with selenium dioxide, followed by sequential treatment with sodium borohydride, methanesulfonyl chloride, and morpholine afforded the morpholinomethyl derivative 30. Catalytic hydrogenation of 23 and 30 with Pd/C yielded the corresponding amino derivatives 24 and 31. Catalytic hydrogenation of 5-cyano-2-methylpyridine (33) with Raney nickel, followed by treatment with acetic anhydride, gave the amide derivative 35. N-Oxidation of 35, followed by rearrangement with acetic anhydride, produced the acetate derivative, 5-[(acetylamino)methyl]-2-(acetoxymethyl)pyridine (37). Repetition of the N-oxidation and rearrangement procedures with compound 37 yielded the diacetate derivative 39. Condensation of compounds 24, 31, and 39 with thiosemicarbazide afforded the respective 3,5-diaminopyridine-, 4-(4-morpholinylmethyl)-5-aminopyridine-, and 5-(aminomethyl)pyridine-2-carboxaldehyde thiosemicarbazones (25, 32, and 40). The most biologically active compounds synthesized were the 5-(methylamino)-, 5-(ethylamino)-, and 5-(allylamino)pyridine-2-carboxaldehyde thiosemicarbazones (8, 17, and 18), which were potent inhibitors of ribonucleotide reductase activity with corresponding IC50 values of 1.3, 1.0, and 1.4 microM and which produced significant prolongation of the survival time of L1210 leukemia-bearing mice, with corresponding optimum % T/C values of 223, 204, and 215 being obtained when administered twice daily for six consecutive days at dosages of 60, 80, and 80 mg/kg, respectively.
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PMID:Synthesis and biological activity of 3- and 5-amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. 869 57

A series of novel platinum(IV) complexes of the type DACH-PtIV-trans-(Y)2-cis-X (where DACH = trans-(1R,2R)-, trans-(1S,2S)-, or cis-1,2-diaminocyclohexane; X = diacetate, oxalate, malonate, methylmalonate, cyclobutanecarboxylate (CBCA), or 1,1-cyclobutanedicarboxylate (CB-DCA); and Y = acetate or trifluoroacetate) has been synthesized and characterized by elemental analysis, IR, and 195Pt-NMR spectroscopy. The compounds have been tested against cisplatin-sensitive L1210/0 leukemia, cisplatin-resistant L1210/DDP leukemia, and M5076 reticulosarcoma cell lines in vivo. Most of these analogs displayed reasonable activity against L1210/0 cells (%T/C = 135 to > 700). There were no gross differences in activity between analogs containing isomers of DACH. Selected compounds were evaluated against L1210/DDP tumor models in which they demonstrated reduced but significant activity compared with activity in the L1210/0 model. Interestingly, complex 20, PtIV(trans-1R,2R-DACH)-trans-(acetate)2-methylmalonate, was highly active against M5076, although it had no activity against the L1210 lines. The results demonstrate that specific combinations of axial and equatorial carboxylate ligands, together with the DACH carrier ligand, can favorably modulate the antitumor properties of platinum complexes and enhance circumvention of cisplatin resistance.
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PMID:Chemical and biological studies on a series of novel (trans-(1R,2R)-, trans-(1S,2S)-, and cis-1,2-diaminocyclohexane)platinum(IV) carboxylate complexes. 901 35

The expression of nitric oxide synthase (NOS) isoforms was investigated in the established ESKOL hairy cell line and in leukemic cells of patients with hairy cell leukemia (HCL). By reverse transcription-polymerase chain reaction (RT-PCR), these cells were found to spontaneously express inducible NOS (iNOS)-specific mRNA, but not endothelial constitutive NOS (ecNOS) mRNA. The iNOS protein was detected by immunofluorescence in the cytoplasm of permeabilized leukemic cells and ESKOL cells, using different anti-iNOS monoclonal antibodies. A protein of 135 kDa was identified by Western blotting in ESKOL and HCL lysates, confirming the presence of an iNOS in these cells. Cytosolic homogenates displayed NOS catalytic activity, as measured by the conversion of 14C-labelled L-arginine into 14C L-citrulline and by detection in situ using the DAF-2DA (diaminofluorescein diacetate) NO-sensitive fluorescent probe. Ligation of CD23 (low affinity IgE receptor) was found to increase iNOS expression in ESKOL and conversely to decrease the percentage of cells undergoing apoptosis, as measured by the percentage of cells expressing annexin V. These results indicate that, as in chronic B cell lymphocytic leukemia cells (B-CLL) a functional iNOS is expressed constitutively in hairy cells that contributes to protecting these tumoral cells from apoptosis.
Leukemia 2000 Apr
PMID:Expression of a functional inducible nitric oxide synthase in hairy cell leukaemia and ESKOL cell line. 1076 57

A murine model of minor histocompatibility antigen-mismatched bone marrow transplantation (BMT) was used to study the role of timing of donor lymphocyte infusion (DLI) in eliciting graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity. We gave DLI at weeks 3 and 12 after BMT and related its ability to induce a GVL effect with (1) evolution of T cell chimeric status and (2) the extent to which DLI could elicit lymphohematopoietic GVH (LHGVH) reactivity. All mice remained free of GVH disease, but only week 3 DLI chimeras exhibited a significant GVL response when challenged with host-type leukemia cells. In these week 3 DLI chimeras, host-reactive T cells were found to proliferate in vivo (5- [and-6]-carboxyfluorescein diacetate, succinimidyl esther [CFSE]-labeled DLI inocula, TCR-Vbeta6(+) T-cell frequency) and T-cell chimerism rapidly converted from mixed into complete donor type, indicating the occurrence of LHGVH reactivity. In week 12 chimeras, DLI elicited none of the activities noted at week 3. Yet, in both instances, splenocytes, recovered following DLI, generated an equally strong antihost proliferative response in a mixed lymphocyte reaction, thereby arguing against a decisive role of regulatory cells. The lack of in vivo LHGVH reactivity after week 12 DLI was associated with a substantially increased level of pre-existing host-type T-cell chimerism. We conclude that elicitation of a GVL effect may require LHGVH reactivity and that the reason why timing of DLI was critical for obtaining LHGVH reactivity and the desired GVL effect may lie in the evolution of chimeric status. A possible direct involvement of residual host-type antigen-presenting cells in eliciting LHGVH reactivity after DLI should be studied using models that allow chimerism analysis in non-T-cell lineages.
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PMID:Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants. 1217 14

We had shown previously that the novel, marine, anticancer compound dehydrothyrsiferol (DHT) does not modulate P-glycoprotein (P-gp) dependent drug efflux. Many chemotherapeutics with clinical impact are substrates for the structurally distant related membrane transport protein MRP1 (multidrug resistance-associated protein 1). Thus, we were interested in analysing the behaviour of DHT and control compounds in specific drug transport of MRP1 overexpressing cells. We established a fluorescence based drug efflux system for specific, functional detection of interference of a test compound in MRP1 mediated drug extrusion. Briefly, MRP1 overexpressing HL60/Adr cells were incubated to uptake and then efflux fluorescent 5(6)-carboxyfluorescein diacetate (CFDA), rhodamine 123 (Rh123), or 3,3-diethylocarbocyanine iodide (DiOC2), respectively. Changes in cell fluorescence intensity after coincubation with the compound of interest were determined by flow cytometry. MRP1 mediated efflux of CFDA was analysed in the presence of DHT, the known substrates genistein, probenecid, and the specific inhibitor MK-571. To exclude unknown P-gp related interference in drug transport, efflux of the fluorescent P-gp substrate DiOC2 and specific inhibition by cyclosporin A (CsA) were analysed. Cytotoxicity of DHT in resistant HL60/Adr cells was found to be even superior to that in the parental HL60 leukaemia cell line. Consequently, DHT did not interfere in MRP1 mediated drug transport. In contrast to DiOC2, rhodamine 123 was not specifically effluxed by P-gp but also by MRP1. Therefore, we propose the MRP1 specific CFDA efflux model as a screening and/or excluding system for MRP1 substrates. Together with previous data our results suggest DHT to be an interesting candidate for further investigation directed towards a drug development regimen.
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PMID:Dehydrothyrsiferol does not modulate multidrug resistance-associated protein 1 resistance: a functional screening system for MRP1 substrates. 1237

We previously reported the isolation of the novel human DENN gene, which is differentially expressed in normal and neoplastic cells. DENN is identical to MADD (mitogen-activated protein kinase-activating death domain), which interacts with tumor necrosis factor receptor 1 through their death domains. DENN is also homologous to Rab3 GEP, a rat Rab3 GDP/GTP exchange protein. Real-time reverse transcription-polymerase chain reaction analysis showed that DENN expression in cancer cell lines was 26-50 times that in normal cells. The Jurkat human leukemia, PLC/PRF/5 human hepatoma, and NS-1 mouse myeloma cell lines as well as the MRC-5 human fetal lung and Vero monkey kidney cell lines were treated successfully with four separate DENN-targeted antisense oligodeoxynucleotides (ODNs) to abrogate DENN expression. Quantitative assessment of cell viability and apoptosis by flow cytometry via fluorescein diacetate and propidium iodide membrane-integrity tests, terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling, and annexin V assays showed that antisense silencing of DENN resulted in markedly more pronounced cell death in cancer cells compared with nonmalignant cells. Antisense-treated cell lines exhibited extensive loss of DNA content, forming distinct sub-G(1) peaks, while cell proliferation diminished significantly. Ultrastructural features of programmed cell death in cells subjected to antisense ODNs were authenticated by electron microscopy. In contrast, transfection of cell lines with a plasmid construct to achieve DENN overexpression augmented cellular proliferation and could reverse the apoptotic effect of antisense and staurosporine treatment. Our findings suggest that DENN is intimately involved in anti-apoptotic and cell-survival processes.
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PMID:Induction of marked apoptosis in mammalian cancer cell lines by antisense DNA treatment to abolish expression of DENN (differentially expressed in normal and neoplastic cells). 1241 May 63


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