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 preparation of thirteen N-acyl and N-acyloxy analogues of two 3,5-bis(arylidene)-4-piperidones were prepared as potential prodrugs of the parent ketones. Approximately half of the compounds demonstrated antileukemic properties when evaluated against murine L1210 lymphoid leukemia cells. Three of the derivatives were more active than or equipotent with the reference drug melphalan. All of the compounds were examined against approximately 55 human tumours representing eight different neoplastic diseases. Not only were most of the compounds more cytotoxic than melphalan but 60% of the derivatives displayed selective toxicity to leukemia. A stability study of six of the candidate prodrugs using 1H NMR spectroscopy revealed that while some decomposition in solution occurred, the parent amine was not liberated.
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PMID:Cytotoxic evaluation of some N-acyl and N-acyloxy analogues of 3,5-bis(arylidene)-4-piperidones. 757 5

Leukaemia inhibitory factor (LIF) is a polyfunctional cytokine active on many cell types. We present here 1H NMR studies on the solution properties and stability of MH35, a chimera of murine and human LIF which can be expressed at high levels in Escherichia coli, thus enabling efficient labelling of the protein with the stable isotopes 13C and 15N. MH35 has 85% sequence identity with human LIF and similar activity in biological assays. The 1H chemical shifts of the 12 conserved aromatic residues and the pKa values of the five conserved histidine residues in MH35 and human LIF are very similar. Temperature dependence studies indicate that both proteins are stable, with significant conformational changes occurring only above 70 degrees C. These results show that these proteins have a similar overall structure and stability and that MH35 is therefore a suitable analogue of human LIF for structural studies in solution.
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PMID:NMR studies of a murine-human chimera of leukaemia inhibitory factor (LIF). Comparison with human LIF. 777 6

Methotrexate (MTX), one of the earliest cancer chemotherapy agents, continues to be used extensively in the treatment of leukemia and a variety of other tumors. The efficacy of this drug results from its facile uptake by cells, rapid polyglutamylation and virtually stoichiometric inhibition of dihydrofolate reductase (DHFR), a key enzyme in cell replication. From the work of a multitude of biochemists, molecular biologists, organic chemists and pharmacologists, much is known about the mode of action of MTX and the mechanisms by which tumors exhibit inherent or acquired resistance to this drug. MTX enters cells primarily by a carrier-mediated active transport system whose principal substrate is 5-methyltetrahydrofolate, and additional glutamates are added to the gamma-position of the parent glutamate moiety. The tight binding of MTX to DHFR is defined from NMR and X-ray crystallographic studies of the enzyme and its drug or substrate complexes, supplemented by site-directed mutagenesis to confirm specific interactions. Resistance to the drug, encountered in cell culture model systems or in cancer patients, can result from an increased level of DHFR (due to gene amplification), mutant DHFR with reduced affinity for MTX, or decreased uptake or polyglutamylation of the drug. Although DHFR is an extremely well-studied enzyme, there is still some uncertainty about its kinetics, mechanism for reduction of folate, multiple forms, and activation by a diverse group of agents. Prodrug forms of MTX, e.g., MTX alpha-phenylalanine, which can be activated by carboxypeptidase A-monoclonal antibody conjugates, offer promise for improved efficacy of the drug by selective targeting to tumors. The large body of information summarized above has aided in the development of other folate antagonists, provides a paradigm for assessing the status of other cancer chemotherapeutic agents in current use, and offers a platform from which to speculate about the future of the field.
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PMID:The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. 794 84

31P NMR spectroscopy was used to study the products of the decomposition of cyclophosphamide (1) in buffered solutions at pH's ranging between 1.2 and 8.6 at 20 degrees C and at pH 7.4 at 37 degrees C. At pH 1.2, 1 undergoes a rapid breakdown (t1/2 = 1.4 days) of the two P-N bonds, giving compounds 2 [HN(CH2CH2Cl)2] and 3 [H2N(CH2)3OP(O)(OH)2] as hydrochlorides. No intermediates were detected. At pH's between 5.4 and 8.6, hydrolysis of 1 during 17 days leads to the sole and previously unknown nine-membered ring compound 13. 13 results from the intramolecular alkylation of 1 giving the bicyclic compound 7 followed by the exothermal hydrolytic breakdown of the P-N bond of its six-membered ring. At pH 2.2 and 3.4, the two hydrolytic pathways coexist since, beside compounds 2 and 3, the hydrochloride of compound 9 [Cl(CH2)2NH(CH2)2NH(CH2)3OP(O)(OH)2] is formed, resulting from the acid-catalyzed breakdown of the P-N bond in the nine-membered ring compound 13. At pH 2.2, the presence of chloride ion affected neither the stability of 1 nor the contribution of the two competing hydrolytic pathways. At pH's ranging from 3.4 to 8.6, there is little degradation of 1 since more than 95% of initial 1 was still present after 7 days at 20 degrees C. Under physiological conditions (pH 7.4, 37 degrees C) after 6 days, 45% of 1 is hydrolyzed (t1/2 = 6.6 days), leading essentially (30% of initial 1) to the nine-membered ring compound 13. The rate of hydrolysis of 13 and the nature of its hydrolysis products were found to depend on pH over the range 0-8.6. After a single ip injection to mice, compounds 3, 9, and 13 were less toxic than 1. They did not exhibit any direct cytotoxic efficacy on the colony-forming capacity of L1210 cells in vitro, and they had no antitumor activity in vivo against P388 leukemia.
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PMID:Chemical and biological evaluation of hydrolysis products of cyclophosphamide. 796 59

The nucleocapsid protein of Moloney murine leukemia virus (NCp10) is a 56-amino acid protein which contains one zinc finger of the CysX2CysX4HisX4Cys form, a highly conserved motif present in most retroviruses and retroelements. At pH > or = 5, NCp10 binds one zinc atom and the complexation induces a folding of the CysX2CysX4HEsX4Cys box, similar to that observed for the zinc-binding domains of HIV-1 NC protein. The three-dimensional structure of NCp10 has been determined in aqueous solution by 600 MHz 1H NMR spectroscopy. The proton resonances could be almost completely assigned by means of phase-sensitive double-quantum-filtered COSY, TOCSY and NOESY techniques. NOESY spectra yielded 597 relevant structural constraints, which were used as input for distance geometry calculations with DIANA. Further refinement was performed by minimization with the program AMBER, which was modified by introducing a zinc force field. The solution structure is characterized by a well-defined central zinc finger (rmsd of 0.747 +/- 0.209 A for backbone atoms and 1.709 +/- 0.187 A when all atoms are considered), surrounded by flexible N- and C-terminal domains. The Tyr28, Trp35, Lys37, Lys41 and Lys42 residues, which are essential for activity, lie on the same face of the zinc finger, forming a bulge structure probably involved in viral RNA binding. The significance of these structural characteristics for the various biological functions of the protein is discussed, taking into account the results obtained with various mutants.
J Biomol NMR 1994 Mar
PMID:Three-dimensional 1H NMR structure of the nucleocapsid protein NCp10 of Moloney murine leukemia virus. 801 31

The first two analogs 5a,b of a new class of neutral large-ring square-planar Pt(II) chelate complexes of the generic structure [Pt(cis-1,4-dach)X2] were synthesized via a refined technique, structurally characterized by NMR (1H, 13C, 195Pt), FAB mass spectrometry, and X-ray crystallography, and evaluated for antitumor activity in vitro and in vivo in sensitive and Pt-resistant murine leukemia cell systems. An X-ray crystal structure analysis confirmed that [Pt(cis-1,4-dach)malonate] 5b is monomeric and that the cis-1,4-diaminocyclohexane (dach) ligand is incorporated in a unique and previously unknown locked boat conformation. Complex 5b crystallized as colorless rectangular plates in the orthorhombic space group Pcmn with Z = 4 and the lattice parameters a = 6.239(1) A, b = 9.965(2) A, and c = 18.437(4) A. Important structural parameters are Pt-O = 2.024(5) A, Pt-N = 2.021(6) A, N-Pt-N = 100 degrees, and N-Pt-O = 85 degrees; R = 0.0515, Rw = 0.0635. Antitumor results in murine tumor models show that the parent molecule 5a (X2 = 2 Cl) (a) is more dose potent than cisplatin against the leukemias and solid tumors examined, (b) possesses significant activity against cisplatin-resistant leukemias, but exhibits partial cross-resistance with cisplatin, and (c) may possess a spectrum of activity different from that of cisplatin. Antitumor test results in vitro indicate that (a) 5a is at least equivalent to cisplatin in dose potency and effectiveness in the leukemia cell systems studied except in the [Pt(1,2-dach)Cl2]-resistant L1210 cell line, (b) the cisplatin-resistant leukemia cell systems exhibit partial cross-resistance to 5a, (c) 5a possesses either comparable or greater cytotoxicity than the reference complexes, CI-973 (3) and bis(platinum) complex 4, and (d) 5a is more effective (approximately 18-fold) than [Pt(1R,2R-dach)Cl2] 2 in inhibiting growth in the Pt(1,2-dach)-resistant L1210 cell line, suggesting that [Pt(cis-1,4-dach)Cl2] is either not recognized as or is not acting as a "typical" Pt(dach) complex. The encouraging antitumor activity of 5a, coupled with a 10-fold higher aqueous solubility compared to [Pt(1R,2R-dach)-Cl2] 2 warrants the following future studies: synthesis of selected analogs, elucidating the nature of Pt-DNA binding sites, the mechanism of action, and the mechanistic basis for the lack of cross-resistance of [Pt(cis-1,4-dach)Cl2] against the [Pt(1,2-dach)Cl2]-resistant L1210 cell line.
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PMID:Synthesis, structural characterization, and antitumor properties of a novel class of large-ring platinum(II) chelate complexes incorporating the cis-1,4-diaminocyclohexane ligand in a unique locked boat conformation. 806 93

The synthesis, characterization, and antitumor activity of a series of platinum(IV) complexes of the type DACH-PtIV(X)2Y (where DACH = trans-dl, or trans-l-1,2-diaminocyclohexane, X = OH or Cl, and Y = oxalato, malonato, methylmalonato, tartronato, ketomalonato, 1,1-cyclopropanedicarboxylato, or 1,1-cyclobutanedicarboxylato, are described. These complexes have been characterized by elemental analysis, HPLC, and infrared and 195Pt NMR spectroscopic techniques. The complexes had good in vitro cytotoxic activity (IC50 = 0.14-7.6 micrograms/ml) and were highly active in vivo against leukemia L1210 cells (%T/C = 152- > 600, cisplatin = 218). In addition, excellent in vivo antitumor activities against B16 melanoma (%T/C = 309), M5076 reticulosarcoma (100% cures) and cisplatin-resistant L1210/DDP (%T/C = 217) cell lines were also exhibited by an analog selected for further evaluation.
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PMID:Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes. 815 10

This study was carried out to investigate the red blood cell and white blood cell deformability index in leukemia which is marked by an uncontrolled increase of leucocytes in the bone marrow as well in peripheral blood. It was observed that leucocytes are less deformable than erythrocytes, and erythrocytes from Chronic Myelogenous Leukemia (CML) patients less deformable than normal erythrocytes. The deformability indexes for lymphoblasts from acute lymphoblastic leukemia and myeloblasts from acute myelogenous leukemia were almost the same and higher than that of granulocytes from chronic myelogenous leukemia. These observations led to the conclusion that the significant increase in the resistance to the flow of blood in vivo in leukemia may be due to the increase in the number of leucocytes which are more rigid than erythrocytes.
Physiol Chem Phys Med NMR 1993
PMID:Cellular deformability studies in leukemia. 815 54

A series of novel water-soluble amine platinum (II) tellurate complexes of the type (A)Pt(II) [TeO2(OH)4], where A = 1,2-diaminocyclohexane (DACH), 1,1-bis(aminomethyl)cyclohexane (AMCH), ethylenediamine (en), or cyclopentylamine (cpa), were prepared either by the reaction of amineplatinum (II) sulfate with barium tellurate or by a direct reaction of (A)Pt(OH)2 with telluric acid. Oxidation of the amine platinum(II) tellurate produced amine platinum(IV) tellurate (A)Pt(IV)trans(Z) [TeO2(OH)4] complexes, where Z = OH or Cl, following oxidation with hydrogen peroxide or with chlorine gas, respectively. Complexes were characterized by elemental analysis, and IR and 195Pt NMR spectroscopy. Against i.p. murine leukemia cells in vivo, some of the complexes displayed good antitumor activity when administered intraperitoneally (i.p.) on days 1, 5, and 9 at their optimal doses. Pt(II) complexes containing R,R-DACH, S,S-DACH, R,R-S,S-DACH, or AMCH produced %T/C of 147 to 288 whereas cis-DACH, en, and cpa complexes were inactive. In the Pt(IV) series, the R,R-DACH complex with axial Cl was highly active (%T/C = 371, 40% cures) compared with the complex with axial OH (%T/C = 135).
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PMID:Synthesis, characterization, and antitumor activity of amine platinum(II) and (IV) tellurate complexes. 816 8

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.
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PMID:Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes. 818 6


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