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)

We report the cytotoxicity toward B16 cells and antitumor activity in three transplantable tumor models of a series of ionic, tetrahedral, bischelated gold diphosphine complexes of the type [Au1(R2PYPR2')2]X, where Y = (CH2)2, (CH2)3, or cis-CH = CH. The anion (X = Cl, Br, I, CH3SO3, NO3, PF6) had little effect upon activity. The R = R' = phenyl complexes 1, 7, and 8 [Y = (CH2)2, (CH2)3, cis-CH = CH, X = Cl] were the most active against P388 leukemia, with an increase in lifespan ranging from 83 to 92% and were also active against M5076 sarcoma and B16 melanoma. Complexes with pyridyl or fluorophenyl substituents had reduced activities. For the latter, 19F and 31P NMR were used to verify the formation of bischelated gold(I) complexes in solution. The reduced activity of the complex with R = Et and R' = Ph and inactivity with R = R' = Et are discussed in terms of their increased reactivity as reducing agents. 31P NMR studies show that [AuI(Et2P(CH2)2PPh2)2]Cl readily reacts with serum, albumin, and Cu2+ ions to give oxidized ligand.
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PMID:Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates. 232 59

Ascorbic acid (vitamin C) is an important intracellular reducing agent. It also has been suggested to be (i) a protective agent against development of cancer, (ii) a therapeutic agent for malignancies and (iii) a mutagen. We have found that high concentrations of ascorbate leads to DNA damage in several in vivo and in vitro situations. Guinea-pigs receiving oral 1-methyl-1-nitrosourea (MNU) were used as a whole animal model. Administration of sodium ascorbate prior to MNU increased strand breakage in pancreatic DNA. Concentrations of ascorbate greater than 0.5 mM increased the frequency of DNA strand breaks caused by MNU in both L1210 murine leukemia cells and guinea-pig pancreatic cells in tissue culture; ascorbate alone led to DNA strand breaks in the latter cells. Investigations of the mechanism of DNA damage were carried out with purified DNA. Ascorbate produced single- and double-strand breaks in plasmid DNA. Cleavage was catalyzed by copper(II), inhibited by catalase and blocked by the presence of thiols. We conclude that superoxide and hydrogen peroxide produced during the oxidation of ascorbate leads to generation of hydroxyl free radicals that can mediate DNA strand scissions and potentiate the effects of alkylating carcinogens.
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PMID:Ascorbate potentiates DNA damage by 1-methyl-1-nitrosourea in vivo and generates DNA strand breaks in vitro. 282 77

Several derivatives and analogs of the recently reported antiproliferative and antitumor agent trans-bis(salicylaldoximato)copper(II) (CuSAO2) have been prepared and tested for antiproliferative activity against L1210 leukemia cells in vitro. The salicylaldimine analog of CuSAO2 had a very strong antiproliferative activity, the 2-day IC50 value being lower than 3 micrograms/ml. The 2,3-dihydroxybenzaldoxime analog was equally active with CuSAO2, while the corresponding 2,5-dihydroxy derivative had a slightly lower activity. The 2,3,4-trihydroxybenzaldoxime derivative had a much lower activity than had the dihydroxybenzaldoxime derivatives. The zinc(II) analog of CuSAO2 had only a low antiproliferative activity. The ligand of CuSAO2, salicylaldoxime, resembles pyridoxal oxime, a vitamin B6 antagonist and a powerful inhibitor of pyridoxal kinase. An attempt to reduce the toxicity of CuSAO2 in vivo with pyridoxal hydrochloride led to increased toxicity.
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PMID:Antiproliferative activity of derivatives of trans-bis(salicylaldoximato)copper(II) in vitro. Some in vivo properties of the parent compound. 294 33

Twenty-three new mitomycin C analogues designed to have increased metal complexing ability were synthesized and tested against P388 leukemia in mice. Their ability to complex Cu(II) was revealed by the shifts in their UV absorption spectra caused by this metal. One analogue was clearly more active than mitomycin C in the antitumor assay and two others had good activity. Correlation between antitumor activity and Cu(II) complexing ability was ambiguous. The most active compounds were either not complexers or they were complexers limited to the 2-(2-pyridyl)alkyl type substituent on N7. A variety of amino acid substituents on N7 showed only weak antitumor activity.
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PMID:Mitomycin C analogues with increased metal complexing ability. 309 33

In the mice of high leukemic strain, sick with natural lymphatic leukemia, levels of copper, zinc and cadmium in blood and inner organs were determined by the method of atomic absorption spectrophotometry. Mice were killed on the 0 day (when 10 weeks old) and after 90, 180 and 270 days of observation. In plasma the level of ceruloplasmin (EC1.12.3.1) was determined. It has been proved that in mice with lymphatic leukemia the levels of copper, zinc and cadmium are higher than in control animals. It was also found out that there is some disturbance in the natural antagonism between these metals. The activity of ceruloplasmin in the course of leukemia was determined. We have also tried to interpret the role of heavy metals in leukemogenesis in mice.
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PMID:[Levels of copper and its antagonists in mice with natural lymphocytic leukemia]. 326 10

The mixed disulfide of methyl mercaptan and L-homocysteine, S-(methylthio)-L-homocysteine (L-SMETH), inhibits the growth of L-1210 leukemia cells in culture at micromolar concentrations. The inhibition is markedly promoted by added cupric ion, but not by ions of other metals, is stereospecific, and is competitive with glutamine. For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy resides in the amination of UTP to CTP. This was confirmed by high performance liquid chromatography analysis of cell extracts, which showed a marked decrease in CTP with increases in the levels of UTP, GTP, and ATP. A major swelling of cells leading to lysis accompanies the inhibition and increases in DNA and protein per cell confirms this unbalanced growth. The chemical basis for this biological interaction is presented.
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PMID:Evidence for a copper:S-(methylthio)-L-homocysteine complex as a glutamine antagonist of cytidine triphosphate synthesis in L1210 murine leukemia cells. 341 27

Copper, zinc, and iron were quantitated in the serum and lymphoid cells of the peripheral blood of healthy children and children with acute lymphocytic leukemia. Copper and iron concentrations in serum and cells were significantly higher and zinc concentration in the cells significantly lower in leukemic patients than in healthy donors, whereas the increase of zinc in the serum was not significant. The concentration of all minerals was higher in T-cell enriched preparations. There was a significant correlation between copper and iron and between copper and zinc, but not between iron and zinc in normal and leukemic lymphocytes. No correlation was demonstrated among the three minerals in the serum. There were no significant differences associated with ethnicity, age, sex, type of leukemia, or number of leukemic cells. However, a group of five children with non-B-, non-T-cell acute lymphocytic leukemia, nonreactive skin tests, and low serum immunoglobulins had high concentrations of copper and iron and low concentration of zinc in their leukemic cells. Since copper, zinc, and iron are associated with lymphocyte maturation and regulation of immune function, these new data will provide a tool for the study of the relationship between changes in concentrations of these metals and the modification of the immune response often present in hematologic cancers.
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PMID:Copper, zinc, and iron in normal and leukemic lymphocytes from children. 345 80

The effect of glutathione depletion on cytotoxicity of the anthracycline daunorubicin, and of a copper:bis-thiosemicarbazone chelate, was examined in the P388 murine leukemia and its anthracycline-resistant subline, P388/ADR. Depletion of intracellular glutathione was accomplished through exposure to buthionine sulfoximine, a specific inhibitor of glutathione synthesis. Cytotoxicity of daunorubicin was not altered by glutathione depletion, while responsiveness to the bis-thiosemicarbazone chelate was thereby enhanced.
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PMID:Intracellular glutathione as a determinant of responsiveness to antitumor drugs. 346 80

Following a wet digestion of 0.5-2.0 ml cerebrospinal fluid in an open system using 2.0 ml nitric acid and 1.0 ml perchloric acid (240 degrees C) and a reduction step with 1.0 ml hydrochloric acid, Selenium can be determined polarographically after adding 100 micrograms Copper(II)-ions to the analyte (15 ml; water/perchloric acid). Selenium concentrations in cerebrospinal fluid of children younger than one year (2.49 +/- 1.67 ng/ml) are significantly higher (p = 0.0074) than those of older children (1.28 +/- 0.97 ng/ml). Independent of the childrens age and diseases the Selenium concentrations correlate distinctly with cell numbers and protein contents. A correlation between Selenium content and cell numbers alone could not be proved. The non-significant differences between the Selenium concentrations in cerebrospinal fluids of children with hydrocephalus, leukemia (with or without involvement of the central nervous system), and other diseases, respectively, may be interpreted by considering the protein content of the cerebrospinal fluid and the age of the children.
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PMID:[Selenium concentration in the cerebrospinal fluid of children]. 347 10

We have previously described an assay to quantify the serum neutralization of bacterial lipopolysaccharide which is based on a spectrophotometric Limulus amoebocyte lysate test (T.J. Novitsky, P.F. Roslansky, G.R. Siber, and H.S. Warren, J. Clin. Microbiol. 21:211-216, 1985). Studies since have shown that serum samples drawn from patients with leukemia and fever, gram-negative or gram-positive bacterial infections, or shock caused by gram-negative bacteria neutralize approximately 10-fold more lipopolysaccharide than do samples from normal controls. These findings suggested that the increased neutralization might reflect an acute-phase response and raised the question of whether it might be under the control of interleukin-1. To answer this question, we studied the neutralization of lipopolysaccharide in serum samples drawn from rabbits before and after the administration of crude interleukin-1, prepared from activated macrophage supernatants, and recombinant human interleukin-1. Crude interleukin-1 induced a 5.7-fold increase in serum neutralization 24 h after intravenous injection, and cloned interleukin-1 induced a 3.0-fold increase (P less than or equal to 0.01 and 0.05, respectively). In individual rabbits given identical doses of crude interleukin-1 on a weight basis, the serum-neutralizing ability correlated significantly with three activities of interleukin-1: rise in temperature (r2 = 0.558; P less than or equal to 0.01), decrease in serum iron (r2 = 0.534; P less than or equal to 0.01), and increase in serum copper (r2 = 0.323; P less than or equal to 0.05). We conclude that the increase in neutralization of bacterial lipopolysaccharide by serum samples drawn from patients with inflammatory states is mediated, at least in part, by interleukin-1, presumably through the induction of acute-phase serum proteins.
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PMID:Role of interleukin-1 in augmenting serum neutralization of bacterial lipopolysaccharide. 349 48


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