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)

In order to synthesize bifunctional antitumor compounds, the interactions of adriamycin with metallocene dichlorides, Cp2MCl2, where M = Zr, Ti, V, have been studied. Using absorption, fluorescence, and circular dichroism measurements, we have shown that adriamycin is able to coordinate to the three metal ions. The interaction of Cp2ZrCl2 and Cp2VCl2 with adriamycin leads to compounds of 1:2 metal:drug stoichiometry, whereas the interaction of Cp2TiCl2 with adriamycin leads to two types of compounds of 1:2 and 1:1 stoichiometry. The Zr-adriamycin complex, which is unable to dissociate, even at a pH lower than 1, does not display antitumor activity against P-388 leukemia. However Ti-adriamycin complexes, which are more susceptible to dissociation in acidic media, exhibit antitumor activity that compares with that of the free drug. These complexes, unlike adriamycin, do not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. In addition, the presence of metal ions promote the binding of the drug to DNA and erythrocyte ghosts.
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PMID:Bifunctional antitumor compounds: interaction of adriamycin with metallocene dichlorides. 253 37

Fe(III) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric and spectroscopic measurements, we have shown that adriamycin and daunorubicin form two well-defined species with Fe(III), which can be formulated as respectively Fe(HAd)3 and Fe(HDr)3. In these formulas, HAd and HDr stand for adriamycin and daunorubicin in which the 1,4-dihydroxy-anthraquinone moiety is half-deprotonated. Both complexes are six-membered chelates. The stability constant is beta = (2.5 +/- 0.5) X 10(28) for both complexes. Interaction with DNA has been studied showing that, despite strong coordination to Fe(III), anthracyclines are able to intercalate between DNA bases pairs, releasing the metal. These complexes display antitumor activity against P 388 leukemia that compares with that of the free drug. Fe(HAd)3, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. Moreover, it is shown that the triferric adriamycin compound so called "quelamycin" is in fact a mixture of Fe(HAd)3 and polymeric ferric hydroxide.
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PMID:Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA, and antitumor activity. 298 53

Fe(III) complex of an antitumoral antibiotic carminomycin has been studied. Using potentiometric and spectroscopic measurements we have shown that carminomycin forms with Fe(III) a well-defined species in which three molecules of drug are chelated to one Fe(III) ion. This occurs with the release of one proton per molecule of drug. Magnetic susceptibility measurements suggest that six oxygen atoms are bound to iron. The stability constant is 3 X 10(34). The in vitro inhibition of P 388 leukemia cell growth by this complex compares with that of the free drug. This complex, unlike the free drug, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.
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PMID:Physicochemical studies of the iron(III)-carminomycin complex and evidence of the lack of stimulated superoxide production by NADH dehydrogenase. 298 12

Pd(II) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric absorption, fluorescence, and circular dichroism measurements, we have shown that adriamycin can form two complexes with Pd(II). The first complex (I) involves two molecules of drug per Pd(II) ion; one of the molecules is chelated to Pd(II) through the carbonyl oxygen on C12 and the phenolate oxygen on C11, and the other one is bound to Pd(II) through the nitrogen of the amino sugar. This complexation induces a stacking of the two molecules of drug. In the second complex (II), two Pd(II) ions are bound to two molecules of drug (A1 and A2). One Pd(II) is bound to the oxygen on the carbons C11 and C12 of molecule A1 and the amino sugar of molecule A2 whereas the second Pd(II) ion is bound to the oxygen on C11 and C12 of molecule A2 and the amino sugar of molecule A1. The same complexes are formed between Pd(II) and daunorubicin. The stability constant for complex II is beta = (1.3 +/- 0.5) X 10(22). Interaction with DNA has been studied, showing that almost no modification of the complex occurred. This complex displays antitumor activity against P-388 leukemia that compares with that of the free drug. Complex II, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase.
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PMID:Metal anthracycline complexes as a new class of anthracycline derivatives. Pd(II)-adriamycin and Pd(II)-daunorubicin complexes: physicochemical characteristics and antitumor activity. 396 54

In mice, there is a correlation between genetically regulated levels of inducible aryl hydrocarbon hydroxylase (AHH) activity and the risk of polycyclic hydrocarbon-induced leukemia or solid tumors. Recent clinical studies suggest a relationship between high AHH activity and lung cancer associated with cigarette smoking (Kouri, R.E., McKinney, C.E., Slomiany, D.J., Snodgrass, D.R., Wray, N.P., and McLemore, T.L. Cancer Res. 42: 5030-5037, 1982). To determine whether there is a similar genetic relationship in humans between inducible AHH and the occurrence of pediatric cancers, we examined AHH activity in mitogen-stimulated benzo(a)anthracene-treated lymphocyte cultures from primary relatives of children with leukemia or solid tumors. Control families (parents and siblings with no history of cancer) comprised friends or neighbors of the proband families. By comparing variance among family members with variance among nonrelated individuals, we conclude that a small, but real, genetic component is detectable. Adjusting for age, smoking history, and the length of time during which the lymphocytes had been cryopreserved, however, we find no difference among 77 leukemia, 71 solid tumor, and 100 control family members with regard to median units (+/- median S.E.) of maximally induced AHH activity per unit of reduced nicotinamide adenine dinucleotide-cytochrome c reductase activity: 0.31 +/- 0.03; 0.28 +/- 0.03; and 0.28 +/- 0.03, respectively. Thus, benzo(a)anthracene-induced AHH activity in cultured mitogen-activated lymphocytes in our study population does not appear to be associated with the risk of occurrence of childhood leukemia or solid tumors.
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PMID:Aryl hydrocarbon hydroxylase inducibility among primary relatives of children with leukemia or solid tumors. 669 48

A class of chromophore-modified anthracenediones with an additional pyrimidine ring incorporated into the chromophore system has been obtained in an attempt to provide compounds with diminished peroxidation activity and thus potentially lowered cardiotoxicity. Their synthesis was carried out by the reaction of 6-amino- or 6-hydroxy-7H-benzo[e]perimidin-7-one with a number of alkylamines. Potent activity was demonstrated in vitro against murine L1210 leukemia cells (equipotent with ametantrone) as well as against P388 leukemia in vivo (% T/C = 130-255). We observed that the benzoperimidines did not stimulate free radical formation, perhaps due to their poor substrate properties for NADH dehydrogenase.
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PMID:6-[(aminoalkyl)amino]-substituted 7H-benzo[e]perimidin-7-ones as novel antineoplastic agents. Synthesis and biological evaluation. 842 Dec 88

The role of lipid peroxidation, intracellular glutathione and Ca2+ concentration in menadione-mediated toxicity was investigated in human hepatoma cell lines, Hep G2 and Hep 3B, and in human leukemia cell lines, CCRF-CEM and MOLT-3. Incubation of these cells with 80 microM menadione at 37 degrees C resulted in depletion of intracellular glutathione, increased intracellular Ca2+, and increased lipid peroxidation, events leading to cell degeneration. The sensitivity of these cells to menadione, in order, was: Hep G2 cells > Hep 3B cells > CCRF-CEM cells and MOLT-3 cells. The extent of menadione-induced lipid peroxidation in different cell types followed the same order as did their susceptibility to menadione-induced cell degeneration. The menadione-induced depletion in glutathione level was in the following sequence: Hep G2 cells > MOLT-3 and CCRF-CEM cells > Hep 3B cells. The extent of the menadione-induced increase in the intracellular Ca2+ concentration was: Hep G2 cells > Molt-3 cells > CCRF-CEM cells and Hep 3B cells. Pre-treatment of Hep G2 cells with 20 mM deferoxamine mesylate, an iron chelator, reduced both the menadione-induced cell degeneration and lipid peroxidation; however, it did not prevent the menadione-induced increase in intracellular Ca2+ nor the depletion of glutathione. These data suggest that menadione-induced cell degeneration is directly linked to lipid peroxidation, and that it is less related to the rise in intracellular Ca2+ and the depletion in glutathione content. Dicumarol (an inhibitor of DT diaphorase) enhanced the capacity of menadione to induce Hep 3B cell degeneration from 71.3% to 86.2% after 120 min of menadione treatment at 37 degrees C, but did not have this effect in Hep G2, CCRF-CEM or MOLT-3 cells. The activities of DT diaphorase were 52.4, 39.6, 1.5 and 1.8 nmol cytochrome c reduced/min/mg protein in Hep G2, Hep 3B, CCRF-CEM and MOLT-3 cells, respectively. The activity of DT diaphorase was much higher in Hep G2 cells than in the other cells. It seems that DT diaphorase may not, as suggested by others, protect against cell degeneration by quinones, such as menadione.
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PMID:Menadione-induced cell degeneration is related to lipid peroxidation in human cancer cells. 953 16

Many chromones, especially those having 2-substituents, manifest a remarkable variety of biological activities, such as the important cytotoxicity against human leukaemia cells, antiallergic, anticancer activities; unfortunately chromones normally disturb mitochondrial bioenergetics. A new 2-styrylchromone has been synthesized by the Baker-Venkataraman method and a classical approach has been used to assess the effects of 2-styrylchromone (3'-allyl-4',5,7-trimethoxy-2-styrylchromone) on rat liver mitochondrial bioenergetic. Mitochondrial respiratory rate and transmembrane potential were measured polarographically using a Clark oxygen electrode and with a selective electrode, respectively. All the disturbance induced by 2-styrylchromone on the enzymatic activities (succinate dehydrogenase, succinate cytochrome c reductase, and cytochrome c oxidase) and in the mitochondrial osmotic volume were determined spectrophotometrically. State 4, state 3, and uncoupled (presence of carbonylcyanide p-trifluoromethoxyphenylhydrazone) respiration rates were decreased by 2-styrylchromone in a concentration-dependent manner. Depression of respiratory activity promoted by 2-styrylchromone is essentially mediated through partial inhibition of succinate cytochrome c reductase. Phosphorylation capacity was strongly depressed as a result of an inhibition on the enzymatic complex (F(0)F(1)-ATPase) and also because of a deleterious effect on the integrity of the mitochondrial membrane, which uncoupled the respiration-generated proton gradient with the proton-driven phosphorylation. The structural integrity of the outside membrane is severely affected since cytochrome c can be released. 2-Styrylchromone uncouples oxidative phosphorylation by an inhibitory action on the redox chain and ATP synthase activity. Additionally, it can release cytochrome c. Cell death can probably result due to the induction of procaspase-9 and other procaspases and by a strong decrease of the available ATP.
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PMID:Interactions of a new 2-styrylchromone with mitochondrial oxidative phosphorylation. 1243 63

We examined the expression profiles of doxorubicin-resistant K562 cells by serial analysis of gene expression (SAGE) to identify novel and/or partially characterized genes that might be related to drug resistance in human leukemia. SAGE complementary DNA (cDNA) libraries were constructed from K562 and doxorubicin-resistant K562 (K562/ADM) cells, and concatamer sequences were analyzed with SAGE 2000 software. We used 9792 tags in the identification of 1076 different transcripts, 296 of which were similarly expressed in K562 and K562/ADM cells. There were 343 genes more actively expressed in K562/ADM than in parental K562 cells and 437 genes expressed less often in K562/ADM cells. K562/ADM cells showed increased expression of well-known genes, including the genes for spectrin beta, eukaryotic translation initiation factor 1A (EIF1A), RAD23 homolog B, laminin receptor 1, and polyA-, RAN-, and PAI-1 messenger RNA-binding proteins. K562/ADM cells showed decreased expression of the genes for fatty acid desaturase 1 (FADS1), hemoglobin epsilon 1, N-myristoyltransferase 1, hemoglobin alpha 2, NADH dehydrogenase Fe-S protein 6, heat shock 90-kDa protein, and karyopherin beta 1. Quantitative reverse transcription-polymerase chain reaction analysis confirmed the increased expression of EIF1A and the decreased expression of FADS1 in K562/ADM cells. Prior to this investigation, such differences in the expression of these genes in doxorubicin-resistant leukemia cells were unknown. Although we do not provide any evidence in the present report for the potential roles of these genes in drug resistance, SAGE may provide a perspective into our understanding of drug resistance in human leukemia that is different from that provided by cDNA microarray analysis.
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PMID:Monitoring the expression profiles of doxorubicin-resistant K562 human leukemia cells by serial analysis of gene expression. 1516 98

Experimental hyperoxia represents a suitable in vitro model to study some pathogenic mechanisms related to oxidative stress. Moreover, it allows the investigation of the molecular pathophysiology underlying oxygen therapy and toxicity. In this study, a modified experimental set up was adopted to accomplish a model of moderate hyperoxia (50% O(2), 96 h culture) to induce oxidative stress in the human leukemia cell line, U-937. Spectrophotometric measurements of mitochondrial respiratory enzyme activities, NMR spectroscopy of culture media, determination of antioxidant enzyme activities, and cell proliferation and differentiation assays were performed. The data showed that moderate hyperoxia in this myeloid cell line causes: i) intriguing alterations in the mitochondrial activities at the levels of succinate dehydrogenase and succinate-cytochrome c reductase; ii) induction of metabolic compensatory adaptations, with significant shift to glycolysis; iii) induction of different antioxidant enzyme activities; iv) significant cell growth inhibition and v) no significant apoptosis. This work will permit better characterization the mitochondrial damage induced by hyperoxia. In particular, the data showed a large increase in the succinate cytochrome c reductase activity, which could be a fundamental pathogenic mechanism at the basis of oxygen toxicity.
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PMID:Mitochondrial damage and metabolic compensatory mechanisms induced by hyperoxia in the U-937 cell line. 1546 33


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