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

Translocations involving chromosome band 11q23, found in acute lymphoid and myeloid leukemias, disrupt the MLL gene. This gene encodes a putative transcription factor with regions of homology to several other proteins including the zinc fingers and other domains of the Drosophila trithorax gene product, and the "AT-hook" DNA-binding motif of high mobility group proteins. We have previously demonstrated that MLL contains transcriptional activation and repression domains using a GAL4 fusion protein system (21). The repression domain, which is capable of repressing transcription 3-5-fold, is located centromeric to the breakpoint region of MLL. The activation domain, located telomeric to the breakpoint region, activated transcription from a variety of promoters including ones containing only basal promoter elements. The level of activation was very high, ranging from 10-fold to more than 300-fold, depending on the promoter and cell line used for transient transfection. In translocations involving MLL, the protein produced from the der(11) chromosome which contains the critical junction for leukemogenesis includes the AT-hook domain and the repression domain. We assessed the DNA binding capability of the MLL AT-hook domain using bacterially expressed and purified AT-hook protein. In a gel mobility shift assay, the MLL AT-hook domain could bind cruciform DNA, recognizing structure rather than sequence of the target DNA. This binding could be specifically competed with Hoechst 33258 dye and with distamycin. In a nitrocellulose protein-DNA binding assay, the MLL AT-hook domain could bind to AT-rich SARs, but not to non-SAR DNA fragments. The role that the AT-hook binding to DNA may play in vivo is unclear, but it is likely that DNA binding could affect downstream gene regulation. The AT-hook domain retained on the der(11) would potentially recognize a different DNA target than the one normally recognized by the intact MLL protein. Furthermore, loss of an activation domain while retaining a repression domain on the der(11) chromosome could alter the expression of various downstream target genes, suggesting potential mechanisms of action for MLL in leukemia.
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PMID:The mixed lineage leukemia (MLL) protein involved in 11q23 translocations contains a domain that binds cruciform DNA and scaffold attachment region (SAR) DNA. 858 57

The scaffold attachment region of the human interferon beta gene (IFN-SAR) inserted into a retroviral vector improved transgene expression in human primary CD4+ and CD8+ T cells, and in primary monocytemacrophages. In T cells, expression of the Maloney murine leukemia virus (Mo-MuLV)-based retroviral vectors was high in activated cells but low in resting cells. Addition of the IFN-SAR sequence enhanced vector expression 2- to 10-fold, and the effect was particularly pronounced in resting T cells. In CD33+CD14+CD4+ monocyte-macrophages derived from transduced hematopoietic stem/progenitor cells (HSPCs) in vitro, the IFN-SAR enhanced vector expression three- to sixfold. We have used the IFN-SAR-containing vectors to express the RevM10 gene, a trans-dominant mutant of the human immunodeficiency virus type 1 (HIV-1) rev gene. Compared with a standard retroviral vector, the IFN-SAR-containing vector was significantly (p < 0.01) more potent at inhibiting HIV-1 replication in infected CD4+ peripheral blood lymphocytes. In monocytes, however, addition of the IFN-SAR did not significantly improve antiviral efficacy. To understand better the reason for the strong effect of the SAR on antiviral efficacy in T cells we have studied the expression of HIV, Mo-MuLV, and Mo-MuLV + SAR vectors in resting and activated cells. While the expression of all three vectors was lower in resting compared with activated cells, the kinetics of the decrease in expression were fastest for the Mo-MuLV vector, followed by the HIV vector and then the Mo-MuLV + SAR vector. Thus, higher level expression of the Mo-MuLV + SAR vector relative to wild-type HIV at all stages of T cell activation is the most likely explanation for the strong antiviral efficacy. Overall, this study demonstrates the utility of the IFN-SAR sequence for achieving high-level retroviral vector expression in lymphoid and myeloid hematopoietic cells.
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PMID:Effect of scaffold attachment region on transgene expression in retrovirus vector-transduced primary T cells and macrophages. 1036 68

Moloney murine leukemia virus-based retroviral vector expression is gradually lost during prolonged in vitro culture of CEMSS T cells. However, when the human beta interferon scaffold attachment region (IFN-SAR) was inserted into the vector immediately upstream of the 3' long terminal repeat (LTR), expression was maintained for the length of the study (4 months). Clonal analysis of the retrovirus vector-infected CEMSS cells showed that SAR-containing retroviral vector expression levels were positively correlated with the proviral copy numbers (P < 0.0001), while there was no correlation between the proviral copy numbers and expression levels in control vector-infected clones. Thirty-three percent of the CEMSS cell clones infected with the control vector showed evidence of partial or complete methylation in the 5' LTR region. In sharp contrast, we detected no methylation in the clones infected with the SAR-containing vector. To demonstrate a direct inhibitory effect of methylation on retroviral vector expression, we have transfected 293 cells with in vitro-methylated proviral DNA. In transiently transfected cells, expression of methylated LTR was reduced but not completely inhibited, irrespective of the presence of the IFN-SAR sequence. In stably transfected cells, however, methylation completely abolished expression of the control vector but not of the SAR-containing vector. Furthermore, the expression of the SAR-containing vector was stable over time, indicating the ability of the SAR sequence to alleviate methylation-mediated transcriptional repression of a vector. This study extends our understanding of the mechanisms of retroviral vector inactivation by methylation and provides insight into a functional role for the SAR elements.
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PMID:Human beta interferon scaffold attachment region inhibits de novo methylation and confers long-term, copy number-dependent expression to a retroviral vector. 1068 82

A series of compounds containing an N-(7-indolyl)benzenesulfonamide pharmacophore was synthesized and evaluated as a potential antitumor agent. Cell cycle analysis with P388 murine leukemia cells revealed that there were two different classes of potent cell cycle inhibitors; one disrupted mitosis and the other caused G1 accumulation. Herein described is the SAR summary of the substituent patterns on this pharmacophore template.
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PMID:A focused compound library of novel N-(7-indolyl)benzenesulfonamides for the discovery of potent cell cycle inhibitors. 1086 86

Aromatic/heterocyclic sulfonamides generally act as strong inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Here we report the unexpected finding that potent aromatic sulfonamide inhibitors of CA, possessing inhibition constants in the range of 10(-8)-10(-9) M (against all the isozymes), also act as efficient in vitro tumor cell growth inhibitors, with GI50 (molarity of inhibitor producing a 50% inhibition of tumor cell growth) values of 10 nM-35 microM against several leukemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. The investigated compounds were sulfanilyl-sulfanilamide-, 4-thioureido-benzenesulfonamide- and benzene-1,3-disulfonamide-derivatives. The mechanism of antitumor action with these sulfonamides is unknown, but it might involve either inhibition of several CA isozymes (such as CA IX, CA XII, CA XIV) predominantly present in tumor cells, a reduced provision of bicarbonate for the nucleotide synthesis (mediated by carbamoyl phosphate synthetase II), the acidification of the intracellular milieu as a consequence of CA inhibition or uncoupling of mitochondria and potent CA V inhibition among others. A combination of several such mechanisms is also plausible. Optimization of such derivatives from the SAR point of view, might lead to the development of effective novel types of anticancer agents/therapies.
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PMID:Carbonic anhydrase inhibitors: aromatic sulfonamides and disulfonamides act as efficient tumor growth inhibitors. 1114 Jun 14

Novel sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) were prepared by reaction of aromatic or heterocyclic sulfonamides containing amino, imino, or hydrazino moieties with N,N-dialkyldithiocarbamates in the presence of oxidizing agents (sodium hypochlorite or iodine). The N,N-dialkylthiocarbamylsulfenamido-sulfonamides synthesized in this way behaved as strong inhibitors of human CA I and CA II (hCA I and hCA II) and bovine CA IV (bCA IV). For the most active compounds, inhibition constants ranged from 10(-8) to 10(-9) M (for isozymes II and IV). Three of the derivatives belonging to this new class of CA inhibitors were also tested as inhibitors of tumor cell growth in vitro. These sulfonamides showed potent inhibition of growth against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. With several cell lines. GI50 values of 10-75 nM were observed. The mechanism of antitumor action with the new sulfonamides reported here remains obscure, but may involve inhibition of CA isozymes which predominate in tumor cell membranes (CA IX and CA XII), perhaps causing acidification of the intercellular milieu, or inhibition of intracellular isozymes which provide bicarbonate for the synthesis of nucleotides and other essential cell components (CA II and CA V). Optimization of these derivatives from the SAR point of view, might lead to the development of effective novel types of anticancer agents.
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PMID:Carbonic anhydrase inhibitors: sulfonamides as antitumor agents? 1131 Jun 5

Four classes of 25 tyrosine protein kinase (TPK) inhibitors were designed and synthesized. Compounds 1-10 were tested to inhibit TPK of HL-60 leukemia cell using 32P-ATP method, and some of them exhibit evident inhibitory activities. Their structure-activity relationship is similar to that of TPK inhibitors reported in literatures. Compounds 11-25 were tested to inhibit TPK of normal rat spleen cell using ELISA method and their SAR is different from that using 32P-ATP method.
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PMID:[Synthesis and biological activity of tyrosine protein kinase inhibitors]. 1159 77

A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC(50) < 5 microM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An alpha-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3'-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
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PMID:Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines. 1240 17

The structure of the anticancer agent 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has been modified through SAR and by incorporating barbituric acid, pyridine, quinoline, and alkylcarboxylic acids into A-007's moieties. Analogue anticancer activity and interacting with CD surface markers on a T-cell leukemia cell line were evaluated and the correlation between SAR and biological properties are discussed.
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PMID:Anticancer activity for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) analogues and their abilities to interact with lymphoendothelial cell surface markers. 1241 72

Pyrrolo[2,1-d][1,2,3,5]tetrazinones 10a-o, compounds that hold the deaza skeleton of the antitumor drug temozolomide, were prepared by reaction of 2-diazopyrroles 9 and isocyanates. Such a synthetic route represents, among those leading to azolotetrazinones reported so far, the only possible one since attempts to cyclize to the title ring system 2-amino-1-carbamoylpyrroles 11 or the mono substituted 2-triazenopyrrole 12 failed. Compounds 10 were screened at the National Cancer Institute (NCI) for their activity against a panel of about 60 human tumor cell lines. Most of them possess remarkable antineoplastic activity having GI(50) values in the low micromolar or sub-micromolar range and reaching, in the case of compound 10d, nanomolar concentrations. The most sensitive cell lines were MDA-N and MDA-MB-435 of the breast sub-panel, and SR, K-562, HL60 (TB) and CCRF-CEM of the leukaemia sub-panel. SAR evaluation and COMPARE computations indicate, for compounds 10, a mechanism of action different from that of temozolomide.
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PMID:Pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones, a new class of azolotetrazines with potent antitumor activity. 1273 82


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