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)

1,4-Dihydroxy-5,8-bis(((2-[(2-hydroxyethyl) amino] ethyl)amino))-9,10-anthracenedione dihydrochloride (mitoxantrone) was tested for antitumor activity against experimental tumors in mice and the results were compared with those of seven antitumor antibiotics: adriamycin (ADM), daunomycin (DM), aclarubicin, mitomycin C (MNC), bleomycin, neocarzinostatin, and chromomycin A3. The drugs were given IP or IV, in general on days 1, 5, and 9 following tumor inoculation. Mitoxantrone given IP at the optimal dose (1.6 mg/kg/day; as a free base) produced a statistically significant number of 60-day survivors (curative effect) in mice with IP implanted L1210 leukemia. The curative effect was not observed with any of the other antibiotics. In the case of IV implanted L1210 leukemia, there was an increase in lifespan (ILS) by more than 100% in the mice following IV treatment with mitoxantrone or DM. In IP implanted P388 leukemia, the curative effect was elicited by IP treatment with mitoxantrone or MMC. In IP implanted B16 melanoma, both the curative effect and a more than 100% ILS in mice that did die were produced by IP treatment with mitoxantrone or ADM. In SC implanted Lewis lung carcinoma, mitoxantrone and ADM administered IV also showed effective antitumor activities and produced a 60% and a 45% ILS, respectively. In conclusion, mitoxantrone and ADM had a wider spectrum of antitumor activity against mouse tumors, including two leukemias and two solid tumors, than did the other drugs; however, mitoxantrone elicited higher antitumor effects than ADM on mouse leukemias, especially on L1210 leukemias. Moreover, mitoxantrone possessed much higher therapeutic indices than ADM against IP implanted P388 (optimal dose/ILS40; greater than 128 versus 15.2) and L1210 (optimal dose/ILS25; 72.7 versus 4.8) leukemias. In addition, mitoxantrone showed moderate activity against DM-resistant L1210 leukemia.
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PMID:Antitumor activity of mitoxantrone against murine experimental tumors: comparative analysis against various antitumor antibiotics. 710 79

6-Ethynyluracil (3) was prepared by two different synthetic procedures. In one approach, 6-formyluracil was reacted with (dibromomethylene)triphenylphosphorane to give 6-(2,2-dibromovinyl)uracil (2), which was silylated and treated with phenyllithium to yield 3. Alternatively, silylated 6-iodouracil was reacted with trimethylsilylacetylene in dry triethylamine in the presence of a palladium/copper catalyst to give 6-[(trimethylsilyl)ethynyl]uracil (5). Compound 5 was converted to 3 in refluxing methanol. At neutral pH, 3 reacted with thiols, such as glutathione, 2-mercaptoethanol, and L-cysteine, but did not react with glycine or L-lysine. This reaction was accompanied by a shift in the UV maximum of 3 from 286 nm to 321-325 nm. The reaction of 3 with 2-mercaptoethanol gave cis-6-[2[(2-hydroxyethyl)-thio]vinyl]uracil as the predominant product. Compounds 2 and 3 inhibited the growth of leukemia L1210, B-16 melanoma, and lewis lung carcinoma cells at concentrations ranging from 1 x 10(-6) to 2 x 10(-5) M. As determined with L1210 cells, the inhibition of growth caused by 2 and 3 was not prevented by the natural pyrimidines, indicating that the agents do not act as antimetabolites.
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PMID:Synthesis and biological evaluation of 6-ethynyluracil, a thiol-specific alkylating pyrimidine. 714 68

A nitrogen mustard analog of propranolol was synthesized as a potential lung-specific antitumor agent. Since dl-propranolol concentrates in lung tissue and beta-blocking activity resides only with the l-enantiomer, the d-modification could serve as a lung-directed carrier for a cytotoxic group. Reaction of 1-(1-naphthyloxy)-3-[bis(2-hydroxyethyl)amino]-2-propanol with thionyl chloride resulted in replacement of all three hydroxyl groups with chlorine. The necessary chlorination selectivity was achieved with p-toluenesulfonyl chloride in dimethylformamide solution to provide propranolol mustard, 1-(1-naphthyloxy)-3-[bis(2-chloroethyl)amino]-2-propanol. Both the trichloro compound and propranolol mustard showed reproducible activity against P-388 leukemia. Neither compound was active against the B16 tumor or Lewis lung carcinoma.
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PMID:Synthesis of propranolol mustard as a possible lung-specific antitumor agent. 735 22

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.
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PMID:Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation. 876 29

Mitoxantrone (1,4-dihydroxy-5,8-bis[2-[(2-hydroxyethyl)amino]ethyl]amino-9,10-anth rac enedione; MXH2) is a novel anticancer agent that is useful in the treatment of leukemia and breast cancer. In contrast to other anthracenedione-based agents, this drug causes fewer side effects, mainly because it is resistant to metabolic reduction. We investigated the interaction between MXH2 and inorganic nitrite (NO2-) in aqueous solutions and found that this drug undergoes acid-catalyzed oxidation by nitrite. The rate of this reaction measured versus [NaNO2] at constant pH or versus pH at constant [NaNO2] was found to be directly proportional to the actual HNO2 concentration, indicating HNO2 to be the major oxidizing species. Involvement of .NO and/or NO2. radicals as minor oxidants is suggested based on the dependence of the rate of oxidation on the presence of air. Spectrophotometric and electron paramagnetic resonance analyses indicate that early products of the reaction are identical to those generated by oxidation of MXH2 by a horseradish peroxidase/hydrogen peroxide system. The major product is hexahydronaphtho[2,3-f]quinoxaline-7,12-dione, which is formed by intramolecular cyclization of one alkylamino side chain in the oxidized, diiminoquinone MX(N) form of the drug. This study shows that MXH2 effectively scavenges HNO2 and possibly other nitrogen oxides. Because these reactive forms of nitrogen may be present in vivo, this property of the drug may be relevant to its biological or perhaps anticancer activities.
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PMID:Acid-catalyzed oxidation of the anticancer agent mitoxantrone by nitrite ions. 896 84

Mitoxantrone [1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl] amino]-9,10-anthracenedione, MXH2] is a novel anticancer agent frequently employed in the chemotherapy of leukemia and breast cancer. Earlier studies have shown that metabolic oxidation to reactive 1,4-quinone or/and 5,8-diiminequinone intermediates may be an important mechanism of activation of this agent, pertinent to its cytotoxic action in vivo. Here we report that in the presence of nitrite ions (NO2-), MXH2 undergoes oxidation by the mammalian enzyme lactoperoxidase (LPO) and hydrogen peroxide and that the process proceeds at a rate that is proportional to NO2- concentration. In contrast, when MXH2 was exposed to LPO/H2O2 in the absence of nitrite, oxidation of the drug was either completely absent or markedly inhibited. These experiments were carried out using concentrated solutions of MXH2 (approximately 100 microM) at near neutral pH where dimers of the drug predominate. We propose that oxidation of MXH2 is mediated by an LPO/ H2O2 metabolite of NO2-, most likely the .NO2 radical. Because in mitoxantrone therapy the drug is administered intravenously, it is directly exposed to nitrogen oxides and other free radicals produced by blood components. It is therefore possible that the ability of mitoxantrone to react with the nitrogen dioxide radical may be relevant to the biological action of the drug in vivo.
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PMID:Lactoperoxidase-catalyzed oxidation of the anticancer agent mitoxantrone by nitrogen dioxide (NO2.) radicals. 943 21

The expression of interleukin-1beta (IL-1beta) messenger RNA (mRNA) in macrophage-like cells cultured on phospholipid polymers was evaluated to determine the extent of the inflammatory response. As phospholipid polymers, poly(2-methacryloyloxyethyl phosphorylcholine(MPC)-co-n-butyl methacrylate(BMA)s (PMBs) were synthesized. Poly(ethylene terephthalate) (PET), poly(2-hydroxyethyl methacrylate) (PHEMA), and segmented poly(ether urethane) (Tecoflex 60) were used as reference biomedical polymers. The protein adsorption onto the polymer surfaces from a cell culture medium was determined. The amount of the total protein adsorbed onto the PMBs was lower than that adsorbed onto the reference polymers, and the amount of adsorbed protein decreased with an increase in the MPC units in the PMBs. Human premyelocytic leukemia cell line (HL-60) was used, and the expression of IL-1beta mRNA was investigated with the reverse transcription polymerase chain reaction (RT-PCR) method. When HL-60 cells were cultured on PMBs, the expression of IL-1beta mRNA in the cells was much less than that on the reference polymers. In particular, the expression of IL-1beta mRNA in HL-60 cells cultured on the PMBs containing more than 10 mol % MPC units was not detected. This corresponded to the reduced amount of adsorbed proteins on the PMB surfaces. These results suggest that the PMBs effectively suppressed the activation and inflammatory response of adherent macrophagelike cells.
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PMID:Suppression of the inflammatory response from adherent cells on phospholipid polymers. 1257 54

The preparation and physicochemical and biological characterization of a novel polyaminoacid hydrogel have been reported. The alpha,beta-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) has been used as a starting polymer for a derivatization reaction with methacrylic anhydride (MA) to give rise to the methacrylate derivative named PHM. Photocrosslinking of PHM has been performed in aqueous solution at 313 nm and in the absence of toxic initiators. PHM-based hydrogel has been characterized by scanning electron microscopy, X-ray diffractometry, swelling measurements in aqueous media; the degradation of PHM-based hydrogel has been evaluated as a function of time in the absence or in the presence of esterase. Besides, the biocompatibility of this hydrogel and of its degradation products has been evaluated by performing in vitro assays on human chronic myelogenous leukaemia cells (K-562), chosen as a model cell line. Finally, ATR-FTIR measurements have showed that interaction between PHM-based hydrogel and each of four plasma proteins (albumin, gamma-globulin, transferrin and fibrinogen) does not cause change in protein conformation thus supporting its potential use as a material to prepare parenteral drug delivery systems.
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PMID:A new biodegradable and biocompatible hydrogel with polyaminoacid structure. 1714 87

One novel neolignan (tetracentronsine; 1), one new indole alkaloid (=3-(2-hydroxyethyl)-1H-indole-5-O-beta-D-glucopyranoside; 2), and two new phenol derivatives, 3-{2-[(beta-glucopyranosyl)oxy]-4,5-(methylenedioxy)phenyl}propanoic acid (3) and methyl 3-{2-[(beta-glucopyranosyl)oxy]-4,5-(methylenedioxy)phenyl}propanoate (4), together with six known compounds were isolated from the stem bark of Tetracentron sinense. Their structures were determined by spectral analysis, including 1D- and 2D-NMR, and MS analyses. These compounds were tested for their cytotoxic activity against human leukaemia cells in vitro. Among them, compound 2, (E)-3-(4-hydroxyphenyl)-N-[2-(4-hydroxyphenyl)ethyl]prop-2-enamide (5), and maslinic acid (6) showed significant inhibitory activities against human leukaemia cells CCRF-CEM and its multidrug-resistant sub-line, CEM/ADR5000, with IC50 values in a range of 7.1 to 29.7 microM.
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PMID:New glycosides from Tetracentron sinense and their cytotoxic activity. 1719 35

In this preliminary work we have prepared a fluorinated polymer capable of solubilizing an appreciable amount of O(2) and, at the same time, maintaining a higher water solubility than perfluoroalkanes investigated as injectable O(2) carriers. In particular, we describe the synthesis and characterization of a new macromolecular conjugate obtained by derivatization of alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) with 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole, called PHEA-F. This new water soluble fluoropolymer was prepared in high yield using a simple procedure. It was characterized by FT-IR and UV-vis spectrophotometry, (19)F-NMR and SEC measurements. O(2) solubility studies on PHEA-F aqueous solutions were carried out at 25 degrees C and 37 degrees C at atmospheric pressure and showed that PHEA-F conjugate, despite its low degree of derivatization in fluorine containing groups (2.60 mol-%), is capable of dissolving 13-15% more O(2) than non-fluorinated PHEA. Moreover, O(2) release in simulated physiological conditions is faster for PHEA-F than for PHEA. The biocompatibility of this conjugate has been evaluated by performing an in vitro viability assay on human chronic myelogenous leukaemia cells (K-562) chosen as a model cell line and in vitro haemolysis experiments on human RBCs. All these properties suggest the potential use of PHEA-F as an artificial O(2) carrier.
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PMID:Fluoropolymer based on a polyaspartamide containing 1,2,4-oxadiazole units: a potential artificial oxygen (O2) carrier. 1754 30


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