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)

The synthesis of several new ethyl 2-substituted-aminothiazole-4-carboxylate analogs is described. The prepared compounds were tested for their in vitro antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and showed potential anticancer activity. Ethyl 2-[3-(diethylamino)-propanamido]-thiazole-4-carboxylate (14) exhibited remarkable activity against RPMI-8226 leukemia cell line with GI50 value of 0.08 microM, and a broad spectrum activity against all the tumor cell lines used with GI50 (MG-MID) value of 38.3 microM. The detailed synthesis and antitumor screening data are reported.
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PMID:2,4-Disubstituted thiazoles, Part III. Synthesis and antitumor activity of ethyl 2-substituted-aminothiazole-4-carboxylate analogs. 1032 87

Interest in Mannich bases of 8-hydroxyquinoline stems from reports of their high potency against human cancer cells. In the search for potential anticancer drug candidates, Mannich bases of 8-hydroxyquinoline (7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline, 7-piperidinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline) were synthesised by reaction with various secondary amines and formaldehyde. They were prepared as hydrochlorides. The cytotoxic activity of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline compounds in the National Cancer Institute in-vitro cancer cell line panel was determined. It was found that they exhibited substantial cytotoxic activity against leukaemia. The log concentration of 7-pyrrolidinomethyl-8-hydroxyquinoline, 7-morpholinomethyl-8-hydroxyquinoline and 7-diethylaminomethyl-8-hydroxyquinoline that inhibited 50% of 60 cell lines' growth were -4.81 M, -5.09 M and -5.35 M, respectively. Compound 7-pyrrolidinomethyl-8-hydroxyquinoline was selected for further in-vivo testing. The electrophysiological effect of 7-pyrrolidinomethyl-8-hydroxyquinoline also was tested in human myeloma cells (RPMI 8226). The outward current was voltage dependent, activating at -40 mV and believed to be the voltage-activated K+ current I(K(V)). 7-Pyrrolidinomethyl-8-hydroxyquinoline (1-30 microM) caused the inhibition of I(K(V)) in a concentration-dependent manner. The IC50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of I(K(V)) is 23 microM. The GI50 value of 7-pyrrolidinomethyl-8-hydroxyquinoline-induced inhibition of cell growth is 14 microM. The results suggest that at least part of the cytotoxicity effect of 7-pyrrolidinomethyl-8-hydroxyquinoline on myeloma cells could be related to blockade of voltage-activated K+ channels.
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PMID:Synthesis and cytotoxicity evaluation of some 8-hydroxyquinoline derivatives. 1041 Dec 13

CD95 (Fas/APO-1) is a member of the TNFR superfamily that induces apoptosis following cross-linking with its cognate ligand, CD95L (FasL/APO-1L) or agonist antibody. The human myeloma cell line, RPMI 8226, has limited sensitivity to CD95-mediated apoptosis, with a maximum of 65% of the population responding. To determine the source of the limited sensitivity to CD95-mediated apoptosis, we isolated multiple clones from the RPMI-8226 cell line by limiting dilution. Analysis of these clones demonstrated that sensitivity to CD95-mediated cell death directly correlated with CD95 expression. Clones with high levels of CD95 expression had greater than 90% cell death, whereas cells with low levels of expression had less than 10% cell death. In contrast, no correlative differences were identified for other members of the DISC complex, or for members of the anti-apoptotic Bcl-2 family. We further examined the sensitivity of the 8226 clones to various cytotoxic agents. Although modest clonal variability was demonstrated in response to the chemotherapeutic drugs, doxorubicin, etoposide (VP-16), and vincristine, there was no correlation between CD95 function and sensitivity to chemotherapeutic drugs. These results indicate that in this cell line, receptor expression is rate limiting in CD95-mediated apoptosis, whereas CD95 expression was not a determinant in drug-induced programmed cell death.
Leukemia 2000 May
PMID:Clonal variability in CD95 expression is the major determinant in Fas-medicated, but not chemotherapy-medicated apoptosis in the RPMI 8226 multiple myeloma cell line. 1080 14

We investigated the effect of ubenimex, which has been demonstrated to have immunomodulating activities, on the proliferation of human leukaemic cell lines (HL 60 and K 562, myelogenic lines, Jurkat, a T-cell line and RPMI 8226, a multiple myeloma cell line) and on human bone marrow mononuclear cells from haematopoietic malignancy patients with acute myeloblastic leukaemia, chronic lymphocytic leukaemia or multiple myeloma. The growth of the myeloid cell lines and of a multiple myeloma cell line, but not the T-cell line, was significantly inhibited by cocultivation with ubenimex in a dose-dependent manner. The results of the experiment with haematopoietic malignancy cells showed inhibitory effects on tumour cells from patients with acute myeloblastic leukaemia and multiple myeloma, but not on those from patients with chronic lymphocytic leukaemia. These findings suggest the usefulness of ubenimex for the treatment of multiple myeloma.
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PMID:Aminopeptidase inhibitor ubenimex inhibits the growth of leukaemic cell lines and myeloma cells through its cytotoxicity. 1109 31

Natural killer (NK) cells can lyse a variety of different tumour cells by exocytosis of perforin, subsequent binding of perforin to the target cell membrane and formation of lytic pores. Some tumour cells, however, are resistant to cellular cytotoxicity. Using the NK-resistant tumour cell lines ML-2, MONOMAC-1, RPMI and L540Cy, we demonstrated that activation of NK cells with interleukin 2 (IL-2) and IL-12 resulted in significant lysis of these tumour targets. To investigate the underlying mechanisms, we isolated the cytotoxic granules from non-activated and IL-2-/IL-12-activated NK cells and compared the killing of K562 leukaemia cells (sensitive to NK cell-mediated lysis) and ML-2 leukaemia cells (resistant to NK cell-mediated lysis). In contrast to K562 cells, which were easily killed by NK-cell granules, ML-2 cells were resistant to granules from non-activated NK cells. However, granules from NK cells activated with IL-2 and IL-12 were able to induce significant tumour cell lysis. Cell death of both K562 and ML-2 cells by granules from activated NK cells was completely blocked by anti-perforin antibodies, indicating that perforin mainly accounts for the lysis induced by NK granules. Comparing granules from non-activated and IL-2-/IL-12-activated NK cells, the increased cell death of ML-2 cells was caused by an improved binding of perforin to the target cell membrane. Functional assays, however, indicated that the differences in perforin binding were not as a result of an augmented production of perforin by activated NK cells. We conclude that activation of NK cells results in an increased binding of perforin and subsequent lysis of tumour cells.
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PMID:Activation of natural killer cells with interleukin 2 (IL-2) and IL-12 increases perforin binding and subsequent lysis of tumour cells. 1155 95

TNF-related apoptosis-inducing ligand (TRAIL) shares significant homology with CD95 (Fas) ligand and has the ability to induce apoptosis in sensitive cells through a caspase-mediated pathway. We have evaluated the activity of purified human recombinant soluble TRAIL (S-TRAIL, comprising residues 114-281; Biomol, Plymouth Meeting, PA, USA) and a leucine zipper construct of TRAIL (LZ-TRAIL; Immunex, Seattle WA, USA) against myeloma cell lines NCI H929, U266, RPMI 8226, the FasL-sensitive Jurkat T cell ALL line, the lymphoblastoid cell line MC/CAR and primary tumour cells from 16 myeloma patients. Furthermore, we examined the relationship between TRAIL-induced apoptosis and TRAIL receptor expression utilising RT-PCR and flow cytometry. Two of three myeloma cell lines and Jurkat were TRAIL sensitive whereas MC/CAR was relatively resistant. Five of 16 (31%) primary tumours demonstrated > or =20% reduction in myeloma cells following TRAIL incubation (20-59%). This did not correlate with prior therapy. Four cell lines (two sensitive) and five primary tumours (two sensitive) demonstrated mRNA expression of the intra-cellular death domain containing TRAIL-R1. Variable expression of the two decoy (TRAIL-R3 and R4) and soluble (osteoprotegerin) receptors was seen and this did not correlate with TRAIL resistance. We conclude that myeloma cell expression of death effector receptors for TRAIL is insufficient to confer sensitivity to TRAIL-induced apoptosis but that in a significant minority of patients, irrespective of prior therapy, tumour cells are sensitive to TRAIL. The further investigation of TRAIL as an adjunct to presently available therapies for myeloma is justified.
Leukemia 2001 Oct
PMID:TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy. 1158 25

Increased angiogenesis has recently been recognized in active multiple myeloma (MM). Since vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two key mediators of angiogenesis, we characterized the production of VEGF, b-FGF and interleukin-6 (IL-6) (a MM growth and survival factor) in MM cell lines and Epstein-Barr virus (EBV) transformed B cell lines from MM patients, patient MM cells, as well as bone marrow stromal cells (BMSCs) from normal healthy donors and MM patients. We detected secretion of VEGF, but no bFGF and IL-6, in MM cell lines (MM.1S, RPMI 8226 and U266); EBV transformed B cell lines from MM patients (IM-9, HS-Sultan and ARH77); MM cell lines resistant to doxorubicin (RPMI-DOX40), mitoxantrone (RPMI-MR20), melphalan (RPMI-LR5) and dexamethasone (MM.1R); and patient MM cells (MM1 and MM2). BMSCs from MM patients and normal donors secreted VEGF, b-FGF and IL-6. Importantly, when MM cells were adhered to BMSCs, there was a significant increase in VEGF (1.5- to 3.1-fold) and IL-6 (1.9- to 56-fold) secretion. In contrast, the bFGF decreased in co-cultures of BMSCs and MM cells. Paraformaldehyde fixation of BMSCs or MM cells prior to adhesion revealed that VEGF was produced both from BMSCs and MM cells, though it may come primarily from BMSCs in some cultures. IL-6 was produced exclusively in BMSCs, rather than MM cells. Moreover, when MM cells were placed in Transwell insert chambers to allow their juxtaposition to BMSCs without cell to cell contact, induction of VEGF and IL-6 secretion persisted, suggesting the importance of humoral factors. Addition of exogenous IL-6 (10 ng/ml) increased VEGF secretion by BMSCs. Conversely, VEGF (100 ng/ml) significantly increased IL-6 secretion by BMSCs. Moreover, anti-human VEGF (1 microg/ml) and anti-human IL-6 (10 microg/ml) neutralizing antibodies reduced IL-6 and VEGF secretion, respectively, in cultures of BMSCs alone and co-cultures of BMSCs and MM cells. Finally, thalidomide (100 microM) and its immunomodulatory analog IMiD1-CC4047 (1 microM) decreased the upregulation of IL-6 and VEGF secretion in cultures of BMSCs, MM cells and co-cultures of BMSCs with MM cells. These data demonstrate the importance of stromal-MM cell interactions in regulating VEGF and IL-6 secretion, and suggest additional mechanisms whereby thalidomide and IMiD1-CC4047 act against MM cells in the BM millieu.
Leukemia 2001 Dec
PMID:Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. 1175 17

An affinity capillary electrophoresis/laser-induced fluorescence (CE/LIF) assay was developed for direct and specific detection of reverse transcriptase (RI) of the type 1 human immunodeficiency virus (HIV-1) using fluorescently labeled single-stranded DNA aptamers as probes. The aptamer used (RT 26) is specific for HIV-1 RT, and it exhibited no cross-reactivity with RTs of the enhanced avian myeloblastosis virus (AMV), the Moloney murine leukemia virus (MMLV), or denatured HIV-1 RT. An affinity complex of RT 26-HIV-1 RT was readily formed, and calibration curves were linear up to 50 nM (6 microg/mL) HIV-1 RT concentration, with both the free probe and complex peak usable for analytical quantitation. Cell culture media (RPMI with 10% fetal bovine serum) interfered with the assay and aptamer-HIV-1 RT binding. Nonspecific binding was observed in low or undiluted culture, necessitating at least 100-fold dilution for analysis of raw culture samples.
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PMID:Detection of human immunodeficiency virus type 1 reverse transcriptase using aptamers as probes in affinity capillary electrophoresis. 1179 82

AIM:To investigate alpha-fetoprotein (AFP) mRNA expression in BEL-7404 human hepatoma cells and the effect of L-4-oxalysine (OXL) on the expression.METHODS: Bel-7404 human hepatoma cells were maintained in RPMI 1640 media.Human AFP cDNA probe was labelled with digoxigenin-11-dUTP by the random primer labelling method. The expression of AFP mRNA in Bel-7404 cells was determined by an in situ hybridization technique with digoxigenin-labelled human AFP cDNA probe. The positive intensities of AFP mRNA in cells were analyzed by microspectrophotometer and expressed as absorbance at 470nm. For the experiment with OXL, cells were incubated with various concentrations of the agent for 72h.RESULTS:Essentially all the hepatoma cells contained AFP mRNA in the cytoplasm,although in various amounts. The specificity of the hybridization reaction was confirmed by control experiments in which the use of Rnase-treated BEL-7404 cells, non-AFP producing cells (HL-60 human leukemia cells) or a nonspecific cDNA probe resulted in negative hybridization. When the cells were treated with OXL (25, 50mg/L), the content of AFP mRNA in the cytoplasm was decreased with the inhibition percentages of 34.3% and 70.1%, respectively (P< 0.05).CONCLUSION:AFP mRNA was expressed in BEL-7404 human hepatoma cells and OXL suppressed AFP mRNA expression in the cells.
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PMID:Expression of alpha fetoprotein messenger RNA in BEL-7404 human hepatoma cells and effect of L-4 oxalysine on the expression. 1181 2

A monosomy 7 leukemia cell line, designated MONO-7, was established from the peripheral blood of a patient with monosomy 7 acute myelocytic leukemia (French-American-British classification M0). The cells were cultured continuously for more than 24 months in RPMI-1640 medium supplemented with 10% heat-inactivated fetal calf serum. The cell line exhibits an unclassified appearance. Cytochemically, alpha-naphthol-acetate esterase and myeloperoxidase are negative. Immunophenotypically, the cell line expresses CD33, CD13, CD56, CD34, CD38, HLA-DR, and CD45, but lacks T and B cell-associated antigens. Karyotypic analysis of the cell line showed only 45,XY,-7. Analysis of the N-ras gene mutation demonstrated identical mutations in fresh leukemic cells and the MONO-7 cell line. Clonal rearrangements of the immunoglobulin heavy-chain gene, T-cell receptor beta-chain gene, or T-cell receptor gamma-chain gene were not found in DNA extracted from MONO-7 cells. The growth of MONO-7 cells in vitro was stimulated by recombinant human granulocyte-macrophage colony-stimulating factor or interleukin 3. To our knowledge, this is the first report of the establishment of a cell line with the karyotype 45,XY,-7 without any other abnormality and with a ras gene mutation.
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PMID:Establishment of a monosomy 7 leukemia cell line, MONO-7, with a ras gene mutation. 1184 95


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