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)

Novel benzimidazole derivatives were synthesized and their pharmacological activities were examined. These compounds showed a good suppressive action on histamine release from rat peritoneal mast cells produced by antigen-antibody reaction, an antagonistic action on guinea pig ileum contraction caused by histamine, an inhibitory action on 5-lipoxygenase in rat basophilic leukemia-1 (RBL-1) cells, and a preventive action on NADPH dependent lipid peroxidation induced by Fe3+-ADP in rat liver microsomes. In addition, 1-[2-[2-(4-Hydroxy-2,3,5-trimethylphenoxy)ethoxy]-ethyl]-2-(4-meth yl-1-homopiperazino)-1H-benzimidazole difumarate (BOM1006) exhibited a dose dependent suppressive action on 48 h homologous passive cutaneous anaphylaxis (PCA) reaction in rats orally administered the drug.
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PMID:Synthesis and biological activities of novel antiallergic agents with 5-lipoxygenase inhibiting action. 1072 60

Methoxymorpholinyl doxorubicin (MMDX; PNU 152243) is a promising doxorubicin derivative currently undergoing clinical evaluation. Previous in vitro studies suggested that the compound undergoes hepatic biotransformation by cytochrome P450 (CYP) 3A into a more cytotoxic metabolite(s). The present study examined the role of CYP3A-mediated metabolism in the in vivo antitumor activity and host toxicity of MMDX in the mouse model and investigated the potential for increasing the therapeutic effectiveness of the drug by inducing its hepatic CYP-catalyzed activation. We found that MMDX cytotoxicity for cultured M5076 tumor cells was potentiated 22-fold by preincubating the drug with NADPH-supplemented liver microsomes from untreated C57BL/6 female mice. A greater (50-fold) potentiation of MMDX cytotoxicity was observed after its preincubation with liver microsomes isolated from animals pretreated with the prototypical CYP3A inducer pregnenolone-16alpha-carbonitrile. In contrast, in vivo administration of the selective CYP3A inhibitor troleandomycin (TAO) reduced both potentiation of MMDX cytotoxicity and the rate of CYP3A-catalyzed N-demethylation of erythromycin by isolated liver microsomes (55.5 and 49% reduction, respectively). In vivo antitumor activity experiments revealed that TAO completely suppressed the ability of 90 microg/kg MMDX i.v., a dose close to the LD10, to delay growth of s.c. M5076 tumors in C57BL/6 mice and to prolong survival of DBA/2 mice with disseminated L1210 leukemia. Moreover, TAO administration markedly inhibited the therapeutic efficacy of 90 microg/kg MMDX i.v. in mice bearing experimental M5076 liver metastases; a complete loss of MMDX activity was observed in liver metastases-bearing animals receiving 40 microg/kg MMDX i.v. plus TAO. However, pregnenolone-16alpha-carbonitrile pretreatment failed to enhance MMDX activity in mice bearing either s.c. M5076 tumors or experimental M5076 liver metastases. Additional experiments carried out in healthy C57BL/6 mice showed that TAO markedly inhibited MMDX-induced myelosuppression and protected the animals against lethal doses of MMDX. Taken together, these findings demonstrate that an active metabolite(s) of MMDX synthesized via CYP3A contributes significantly to its in vivo antitumor activity and host toxicity.
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PMID:In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A. 1086 16

6-Chloropurine derivatives of gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 3a, gamma-(Z)-ethylidene-2-methoxy-3-(4-nitro)benzyloxybutenolide 3b, gamma-(Z)-ethylidene-2-(4-nitro)benzyloxy-3-methoxybutenolide 3c, gamma-(Z)-ethylidene-2,3-di(4-nitro)benzyloxybutenolide 3d, and dimethylphosphono-gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 11 as well as the adenine derivative of gamma-(Z)-ethylidene-2,3-dimethoxybutenolide 6 were synthesized. The key steps in the high-yield synthesis of 6 involved hydration/dehydration of the C(4)=C(5) in the precursor 3a. In the presence of NH4OH at elevated temperature, 3a underwent a reverse Michael-type addition with water to produce hydrate 5. At 37 degrees C, 6 was also hydrated in the presence of S-adenosyl-L-homocysteine hydrolase to afford 5. Butenolide 6 exhibited an inhibitory property toward the enzyme. Such type II (enzyme-mediated addition of water across C(4)=C(5)) mechanism is the first example of "enzyme-substrate intermediate" inactivation of S-adenosyl-L-homocysteine hydrolase. In contrast with type I mechanism-based inactivation, reduction of enzyme-bound NADP(+) to NADPH was not observed. Upon treatment with HCl, stereoselective dehydration of 5 occurred to give the target molecule 6. At ambident temperature, 3a was hydrated in the presence of NH4OH or pig liver esterase to produce 6-chloropurine derivative 4. An unambiguous proof of the structures of 3-5 was obtained by X-ray crystallographic analysis. For the synthesis of phosphonate derivative 11, the key step involved chlorination of phosphonate 9 by use of CF3SO2Cl and 1,8-diazabicyclo[5.4.0]undec-7-ene in CH2Cl2. 6-Chloropurine-containing butenolide 3d, 6-chloropurine derivative of 4-hydroxybutenolide 4, and adenine-containing 4-hydroxybutenolide 5 did not show anticancer and antiviral activities. 6-Chloropurine-containing ethylidene-2,3-dialkoxybutenolides 3a-c and phosphonate 11, however, exhibited inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. They were also notably active toward thymidine kinase-deficient varicella-zoster virus (TK(-)VZV). Adenine-containing ethylidene-2,3-dimethoxybutenolide 6 exhibited marked selectivity in cytostatic activity against the murine leukemia (P388) cell line.
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PMID:Synthesis and biological evaluation of purine-containing butenolides. 1135 10

We have designed and synthesized new 5-lipoxygenase inhibitors, fluorinated 3,4-dihydroxychalcones, and evaluated their biological activities with respect to antiperoxidation activity and in vitro antitumor activities. All fluorinated chalcones tested showed 5-lipoxygenase inhibition on rat basophilic leukemia-1 (RBL-1) cells and inhibitory action on Fe(3+)-ADP induced NADPH-dependent lipid peroxidation in rat liver microsomes. The potencies were comparable or better to that of the lead 3,4-dihydroxychalcone. 6-Fluoro-3,4-dihydroxy-2',4'-dimethoxy chalcone (7) was the most effective compound in the in vitro assay using a human cancer cell line panel (HCC panel) consisting of 39 systems.
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PMID:Synthesis and biological activities of fluorinated chalcone derivatives. 1181 58

All-trans retinoic acid (ATRA) combined with granulocyte macrophage colony-stimulating factor (GM-CSF) synergistically increases superoxide-generating activity in human myeloblastic leukemia ML-1 cells. ATRA is known to increase the expression of some NADPH components; however, little is known about the effect of GM-CSF on the expression of these components. We examined the expression of NADPH oxidase components in ML-1 cells treated with ATRA, GM-CSF, or a combination of ATRA and GM-CSF. Expression of p47phox and gp91phox proteins increased markedly after treatment with both reagents. p47phox expression was increased by ATRA alone, and the expression was increased synergistically by the combination of ATRA with GM-CSF. gp91phox was increased by ATRA or GM-CSF alone. The expression of p47phox and gp91phox mRNA underwent similar changes to those seen in protein level. These results indicate that GM-CSF induces expression of gp91phox and enhances ATRA-induced p47phox expression. We speculate that the remarkable induction of gp91phox and p47phox protein is associated with an increase in superoxide-generating activity due to the synergistic effect of ATRA plus GM-CSF.
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PMID:GM-CSF induces expression of gp91phox and stimulates retinoic acid-induced p47phox expression in human myeloblastic leukemia cells. 1222 97

Because of the limited availability of human tissues, leukemia cell lines are often utilized as the models for human leukocytes. In this study, we investigated the NADPH-dependent reductases and polyol pathway in commonly utilized human leukemia cell lines. The relative amounts of aldose and aldehyde reductases were estimated by separating two enzymes with chromatofocusing. The flux of glucose through the polyol pathway was examined by 19F-NMR using 3-fluoro-3-deoxy-D-glucose (3FG) as substrate. Sugar alcohol analysis was conducted by gas chromatography. In myelocytic leukemia cells, the major reductase was aldehyde reductase, and levels of aldose reductase were extremely low. Although lymphocytic cells also contained both aldose and aldehyde reductases, the levels of aldose reductase appeared to be higher in lymphocytic cells than myeolcytic cells. In two lymphocytic cells MOLT-4 and SKW6.4, aldose reductase is clearly dominant. When incubated in medium containing D-galactose, all cell lines quickly accumulated galactitol. There was correlation between galactitol levels and aldose reductase levels. The aldose reductase inhibitor FK 366 significantly reduced the formation of galactitol. 19F-NMR of the cells cultured with 3FG as substrate demonstrated the formation of 3-fluoro-3-dexoy-sorbitol in all the cell lines examined in this study. The relative amounts of sorbitol and fructose varied significantly among the cells. The data confirm that the polyol pathway is present in both myelocytic and lymphocytic leukemia cell lines. However, there is a large variation among the cell lines in the levels of enzymes and flux of glucose through the polyol pathway.
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PMID:NADPH-dependent reductases and polyol formation in human leukemia cell lines. 1260 23

The purpose of this study was to use the proteomics approach, which is based on high resolution two-dimensional electrophoresis coupled with multivariate correspondence analysis and mass spectrometry, to classify objectively the biochemical basis of the anti-cancer activity of the synthetic cyclin-dependent kinase inhibitor, bohemine (BOH). The changes in the cell cycle and corresponding protein composition of the A549 human lung adenocarcinoma cell line after treatment with BOH were evaluated and proteins differentially expressed in the BOH treated A549 cells, compared to the untreated A549 counterparts, were selected. Thirteen of these candidate proteins associated with the drug effects in vitro were identified by mass spectrometry. Many of these proteins fall into one of three functional categories: i) metabolic pathways (glycolysis, nucleic acid synthesis and NADPH production), ii) stress response and protein folding, and iii) cytoskeleton and exocytosis. Changes in protein expression patterns corresponded to a higher resistance of A549 lung carcinoma cells to BOH when compared to the CEM leukaemia cell line. These protein changes reflect a fine balance of the resistant versus the susceptible phenotype in response to the drug. Since BOH is a selective cyclin-dependent kinase inhibitor, changes in the protein expression pattern can be more generally associated with cell cycle regulation as evidenced by inhibition of cell cycling in A549 cells. Our conclusions further underline the importance of cell cycle control in both the cellular signalling and metabolic pathways.
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PMID:Application of proteomics in the search for novel proteins associated with the anti-cancer effect of the synthetic cyclin-dependent kinases inhibitor, bohemine. 1262 83

Thirteen structural analogs of the potent nonpolyglutamatable dihydrofolate reductase inhibitor N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, the para-aminobenzoyl moiety, or the 9,10-bridge were evaluated for the ability to inhibit human recombinant dihydrofolate reductase (DHFR), to utilize the reduced folate carrier (RFC) for influx, and to inhibit the growth of CCRF-CEM human leukemia cells in culture. In spectrophotometric assays of the kinetics of the reduction of dihydrofolate by DHFR in the presence of NADPH, these compounds had K(i) values ranging from 0.2 to 1.3pM, and thus were not greatly different in potency from the parent drug PT523. By comparison, the K(i) values of aminopterin (AMT), methotrexate (MTX), and 10-ethyl-10-deazaaminopterin (EDX) were 3.7, 4.8, and 11pM. In assays of competitive inhibition of [3H]MTX influx into CCRF-CEM cells, the K(i) values ranged from 0.21 to 7.3 micro M, as compared with 0.71, 5.4, and 1.1 micro M for PT523, AMT, and EDX. The K(t) for MTX was also re-analyzed and found to be 4.7 micro M, in better agreement with the literature than our previously reported value of 7.1 micro M. The IC(50) values of these compounds as inhibitors of the growth of CCRF-CEM cells after 72hr of drug exposure ranged from 0.53 to 55nM, and were qualitatively consistent with the other results.
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PMID:Further studies on the interaction of nonpolyglutamatable aminopterin analogs with dihydrofolate reductase and the reduced folate carrier as determinants of in vitro antitumor activity. 1273 54

The ability of the carcinogenic environmental toxin pentachlorophenol (PCP, 1) to react with DNA bases has been assessed using MS and NMR. Treatment of PCP (100 microM) with horseradish peroxidase (HRP/H(2)O(2)) or myeloperoxidase (MPx/H(2)O(2), from human leukocytes) in the presence of excess deoxyguanosine (dG, 2 mM) led to the isolation and identification of the oxygen-bonded C8-dG nucleoside adduct 4. The reaction was absolutely specific for dG; no detectable adduct(s) was observed from HRP/H(2)O(2) and PCP in the presence of deoxyadenosine, deoxycytidine, or thymidine. Formation of 4 was also specific for peroxidase activation that is known to oxidize PCP into the phenoxyl radical. Treatment of PCP/dG with rat liver microsomes (RLM) failed to generate 4; instead, an adduct derived from the benzoquinone electrophile tetrachloro-1,4-benzoquinone (chloranil) was observed in the extracted ion chromatogram from the RLM/NADPH-treated PCP/dG sample. The adduct 4 is the first structurally characterized O-bonded phenolic DNA nucleoside adduct and highlights the ambident electrophilicity of phenoxyl radicals (O- vs C-) in reaction at C8 of dG, as we have previously demonstrated that the para-chlorophenolic toxin, ochratoxin A (2), reacts at C8 of dG to give the C-bonded adduct 3 via the intermediacy of the OTA phenoxyl radical. Given that PCP is known to induce DNA adduct formation in vivo and human exposure has been linked to incidences of leukemia, the adduct 4 could play a key role in PCP-mediated carcinogenesis.
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PMID:An oxygen-bonded c8-deoxyguanosine nucleoside adduct of pentachlorophenol by peroxidase activation: evidence for ambident c8 reactivity by phenoxyl radicals. 1287 Aug 83

The change in cellular reducing potential, most likely reflecting an oxidative burst, was investigated in arachidonic acid- (AA) stimulated leukocytes. The cells studied included the human leukemia cell lines HL-60 (undifferentiated and differentiated into macrophage-like and polymorphonuclear-like cells), Jurkat and Raji, and thymocytes and macrophages from rat primary cultures. The oxidative burst was assessed by nitroblue tetrazolium reduction. AA increased the oxidative burst until an optimum AA concentration was reached and the burst decreased thereafter. In the leukemia cell lines, optimum concentration ranged from 200 to 400 microM (up to 16-fold), whereas in rat cells it varied from 10 to 20 microM. Initial rates of superoxide generation were high, decreasing steadily and ceasing about 2 h post-treatment. The continuous presence of AA was not needed to stimulate superoxide generation. It seems that the NADPH oxidase system participates in AA-stimulated superoxide production in these cells since the oxidative burst was stimulated by NADPH and inhibited by N-ethylmaleimide, diphenyleneiodonium and superoxide dismutase. Some of the effects of AA on the oxidative burst may be due to its detergent action. There apparently was no contribution of other superoxide-generating systems such as xanthine-xanthine oxidase, cytochromes p-450 and mitochondrial electron transport chain, as assessed by the use of inhibitors. Eicosanoids and nitric oxide also do not seem to interfere with the AA-stimulated oxidative burst since there was no systematic effect of cyclooxygenase, lipoxygenase or nitric oxide synthase inhibitors, but lipid peroxides may play a role, as indicated by the inhibition of nitroblue tetrazolium reduction promoted by tocopherol.
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PMID:Arachidonic acid triggers an oxidative burst in leukocytes. 1457 10


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