UMLS:C0023418 - FACTA Search

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)

The properties of a series of methotrexate analogs containing 2,omega-diaminoalkanoic acids have been investigated. The compounds were potent inhibitors of dihydrofolate reductase but, unlike methotrexate, they were also inhibitors of mammalian folylpolyglutamate synthetases. The potency of synthetase and reductase inhibition increased with increasing length of the 2,omega-diaminoalkanoate moiety. The most cytotoxic compound and the most potent inhibitor of both dihydrofolate reductase (I50 = 2.5 to 4 nM) and folylpolyglutamate synthetase (Ki ca. 4 microM) contained 2,5-diaminopentanoic acid (ornithine). These compounds were 70- to 100-fold less cytotoxic than methotrexate to human leukemia cell lines; however, they retained their potency against sublines resistant to methotrexate via defective transport. Their dual loci of enzyme inhibition and their efficacy against methotrexate transport-defective cell lines indicate that these compounds may be an important new class of antifol.
...
PMID:Folylpolyglutamate synthetase inhibition and cytotoxic effects of methotrexate analogs containing 2,omega-diaminoalkanoic acids. 242 84

The Boon-Leigh procedure, involving condensation of a 6-chloro-5-nitropyrimidine (22) with an alpha-amino ketone (20 or 21) followed by reduction of the nitro group, cyclization, and L-glutamylation, led to the formation of 11-deazahomofolate (29) and its 10-methyl derivative (30). The corresponding (6R,S)-5,6,7,8-tetrahydro (4, 5) and 7,8-dihydro (31, 32) derivatives were prepared by catalytic hydrogenation. (6S)-11-Deazatetrahydrohomofolate was prepared from 29 by enzymatic reduction. Compounds 29 and 30 had little effect (IC50 greater than 2 x 10(-5) M) on Lactobacillus casei glycinamide ribonucleotide (GAR) formyltransferase but (6R,S)-11-deazatetrahydrohomofolate (4) is a potent inhibitor of this enzyme (IC50 = 5 x 10(-8) M). It is at least 100 times more inhibitory than 33, the 6S compound, indicating that the 6R component of the mixture having the unnatural configuration at C6 (34) is responsible for the potent inhibition. Compound 4 is a much weaker inhibitor of murine (L1210) and human (MOLT-4) leukemia cell GAR formyltransferases (IC50 greater than 1 x 10(-5) M). (6R,S)-11-Deaza-10-methyltetrahydrohomofolate (5) (IC50 = 1.1 x 10(-5) is 200 times weaker than 4 against L. casei GAR formyltransferase. However, 11-deaza-10-methyldihydrohomofolate (32) is more inhibitory (IC50 = 5.5 x 10(-7) M) than 5 or 30. None of the compounds showed inhibition of L. casei aminoimidazolecarboxamide ribonucleotide (AICAR) formyltransferase, dihydrofolate reductase, or thymidylate synthase. The dihydro derivatives 31 and 32 are 5% as active as dihydrofolate as substrates for L. casei dihydrofolate reductase. Compound 4 showed moderate inhibition of the growth of L. casei, Streptococcus faecium, MOLT-4 cells, and MCF-7 human breast adenocarcinoma cells.
...
PMID:Folate analogues. 31. Synthesis of the reduced derivatives of 11-deazahomofolic acid, 10-methyl-11-deazahomofolic acid, and their evaluation as inhibitors of glycinamide ribonucleotide formyltransferase. 249 18

The antiretroviral action of 2',3'-dideoxycytidine (ddCyd) depends on its intracellular conversion to the 5'-triphosphate metabolite ddCTP. The effect of natural pyrimidines and pyrimidine nucleosides, as well as of a number of inhibitors of pyrimidine nucleotide synthesis (i.e., N-(phosphonacetyl)-L-aspartate, 6-azauridine, pyrazofurin, 3-deazauridine, and hydroxyurea) on the metabolism of the potent anti-human immunodeficiency virus drug ddCyd has been investigated in human and murine cell lines. Deoxycytidine (dCyd) and cytidine (Cyd) effectively blocked the intracellular phosphorylation of ddCyd: dCyd by competition with ddCyd for 2'-deoxycytidine kinase, and Cyd probably by competition with the higher nucleoside mono- and diphosphate kinases. These conclusions are supported by the observations that (i) the cytostatic effects of ddCyd against human Molt/4F cells are significantly reversed by dCyd; (ii) the antiviral effects of ddCyd against hman immunodeficiency virus-infected human ATH8 cells are reversed by dCyd and Cyd; (iii) phosphorylated metabolites of ddCyd could not be detected in a 2'-deoxycytidine kinase-deficient murine leukemia (L1210)/araC cell line; and (iv) ddCyd lacked any cytostatic effect against this araC-resistant L1210 cell line. In contrast to dCyd and Cyd, thymidine (dThd) stimulated formation of phosphorylated ddCyd metabolites. The degree of this stimulation proved dependent on preincubation time and dThd concentration. There was a correlation between the increased ddCTP levels upon preincubation of the cells with dThd, and decreased dCyd-5'-triphosphate pools, presumably caused by inhibition of cytidine-5' -diphosphate reductase by dThd-5'-triphosphate. In an attempt to discover compounds other than dThd that are able to stimulate ddCTP formation, a number of inhibitors of pyrimidine nucleotide metabolism were also studied. Under our experimental conditions, 3-deazauridine and hydroxyurea proved equally as effective as dThd in stimulating ddCyd phosphorylation. Finally, we could demonstrate that dThd significantly enhanced the protective effect of ddCyd against human immunodeficiency virus-infected ATH8 cells.
...
PMID:2',3'-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis. 282 94

The number of gene assignments to human chromosome 20 has increased slowly until recently. Only seven genes and one fragile site were confirmed assignments to chromosome 20 at the Ninth Human Gene Mapping Workshop in September 1987 (HGM9). One fragile site, 13 additional genes, and 10 DNA sequences that identify restriction fragment length polymorphisms (RFLPs), however, were provisionally added to the map at HGM9. Five mutated genes on chromosome 20 have a relation to disease: a mutation in the adenosine deaminase gene results in a deficiency of the enzyme and severe combined immune deficiency; mutations in the gene for the growth hormone releasing factor result in some forms of dwarfism; mutations in the closely linked genes for the hormones arginine vasopressin and oxytocin and their neurophysins are probably responsible for some diabetes insipidus; and mutations in the gene that regulates both alpha-neuraminidase and beta-galactosidase activities determine galactosialidosis. The gene for the prion protein is on chromosome 20; it is related to the infectious agent of kuru, Creutzfeld-Jacob disease, and Gertsmann-Straussler syndrome, although the nature of the relationship is not completely understood. Two genes that code for tyrosine kinases are on the chromosome, SRC1 the proto-oncogene and a gene (HCK) coding for haemopoietic kinase (an src-like kinase), but no direct relation to cancer has been shown for either of these kinases. The significance of non-random loss of chromosome 20 in the malignant diseases non-lymphocytic leukaemia and polycythaemia vera is not understood. Twenty-four additional loci are assigned to the chromosome: five genes that code for binding proteins, one for a light chain of ferritin, genes for three enzymes (inosine triphosphatase, s-adenosylhomocysteine hydrolase, and sterol delta 24-reductase), one for each of a secretory protein and an opiate neuropeptide, a cell surface antigen, two fragile sites, and 10 DNA sequences (one satellite and nine unique) that detect RFLPs.
...
PMID:The map of chromosome 20. 307 44

Following therapeutic administration, cyclophosphamide and Adriamycin are biotransformed to reactive metabolites, some of which are responsible for undesirable systemic toxicities of these chemicals, whereas others are responsible for their chemotherapeutic effectiveness. Microsomal mixed function oxidases activate cyclophosphamide to produce phosphoramide mustard and acrolein, while cytochrome reductase and xanthine oxidase are capable of transforming Adriamycin and forming free radicals. These reactive metabolites produce unwanted toxic side effects; however, their action may be partially ameliorated by the concomitant administration of thiols. In this study we evaluated the therapeutic activity of combinations of mesna (2-mercaptoethanesulfonate) with cyclophosphamide or Adriamycin in mice with a variety of transplantable tumors (L1210 and P-388 leukemia, Lewis lung and colon 26 carcinoma, B16 melanoma, and M5076 sarcoma). In all cases the administration of mesna prior to cyclophosphamide or Adriamycin treatment did not reduce the antitumor effectiveness of these agents and in some instances (C57BL/6 mice with B16 melanoma or M5076 sarcoma) small improvements were observed. Therefore, the addition of thiols, to reduce effectively the buildup of toxic metabolites of cyclophosphamide or Adriamycin may result in the improved therapeutic effectiveness for these agents in the treatment of cancer.
...
PMID:Combinations of mesna with cyclophosphamide or adriamycin in the treatment of mice with tumors. 310 25

L1210 leukemia is a murine leukemia which is associated with anemia and marked neutrophilia. In order to determine the significance of free radicals (FR) in this disorder, we determined the presence and localization of free radical scavengers (FRS) and scavenger-like systems in L1210 leukemia cells obtained in vivo and from in vitro cultures. FR are metabolized or detoxified by certain FRS such as glutathione (GSH and GSSG), superoxide dismutase (SOD) and enzymes such as epoxide hydrolase (EH). In all cases specific fractions of L1210 cells, bone marrow and liver were examined for FR/FRS levels. Reduced (GSH) and oxidized (GSSG) glutathione were measured fluorometerically using o-opthalaldehyde (OPT). SOD was determined colorimetrically utilizing pyrogallol by substrate autolysis inhibition, and EH was determined by utilizing [3H] styrene oxide as a substrate. Ratios of GSH/GSSG in fractions prepared from in vivo and in vitro L1210 cells showed a predominance of GSH-reductase with the highest activity in mitochondria (ratio = 15 vs. 10). Normal liver showed a similar pattern whereas, leukemic liver showed altered GSH/GSSG ratios in mitochrondria and microsomes. Leukemic bone marrow showed a predominance of GSH-reductase in all fractions. EH activity was highest in microsomal fractions obtained from L1210 cells grown in vitro and found to become increased in both the mitrochondrial (100%) and microsomal (200%) fractions when cells were exposed to retinoic acid (RA) in culture. SOD activity in the cytosolic (21.2 U SOD/mg) and mitochondrial (12 U SOD/mg) fractions whereas, leukemic liver showed a significant decrease in activity in all fractions compared to normals. SOD was determined in fractions taken from L1210 cells in vivo and in vitro. Results demonstrated detectable but reduced SOD activity in the L1210 cell fractions as contrasted with liver activity. Results from these studies indicate that certain FRS systems are functional in L1210 leukemic animals. Furthermore, variations in the ratios or levels may be of significance in the leukemic and hematological states.
...
PMID:The significance of free radicals and free radical scavengers in L1210 leukemia. 322 4

The metabolic fate of prostaglandin E2 (PGE2) was examined in human HL-60 leukemia cells. Cytosolic fractions obtained from dimethylformamide treated HL-60 granulocytes rapidly convert exogonous PGE2 to 15-keto-PGE2. The strict requirement for NAD coupled with other characteristics of the reaction indicate that the enzyme is the NAD-dependent 15-prostaglandin dehydrogenase (15-PGDH). When intact cells are incubated with 3H-PGE2, both 15-keto-PGE2 and its subsequent metabolite, 13,14-dihydro-15-keto-PGE2 are produced. Thus, HL-60 cells express two enzymes of the major prostaglandin catabolic pathway, 15-PGDH and ketoprostaglandin delta 13-reductase.
...
PMID:Metabolism of prostaglandin E2 by human HL-60 leukemia cells. 347 88

Through the use of drug-adapted tissue culture cells, correlations have been observed between the level of specific enzymes and drug resistance. Drug resistance, however, may be due to multiple factors. To test whether the activity of daunorubicin reductase or NADPH diaphorase independently influences in vitro daunorubicin-induced cytotoxicity, we developed somatic cell hybrid clones to partially isolate these factors. This was accomplished by fusing daunorubicin-resistant myeloblast cells obtained from a patient with monosomy 7 leukemia to a daunorubicin-sensitive Chinese hamster cell line. The in vitro cytotoxicity of daunorubicin was compared in hybrid clones having variable enzyme activities; the concentrations of daunorubicin that inhibited the growth of clones by 50% did not differ by more than 2-fold, whereas daunorubicin reductase activities and NADPH diaphorase isozyme activities differed by more than 100- and 15-fold, respectively. These large differences in enzymatic activity were obtained in part by the suppression of specific hamster genes, indicating a regulatory control mechanism for xenobiotic enzymes. Our findings suggest that in this system substantial intercellular variation in the activity of these xenobiotic enzymes does not independently influence cellular resistance to daunorubicin.
...
PMID:Use of somatic cell hybrids to analyze role of specific enzymes in daunorubicin cytotoxicity. 354 57

Azelaic acid (C9- -dicarboxylic acid) is a competitive inhibitor of tyrosinase and some oxidoreductase in vitro, and in vivo has a beneficial effect on lentigo maligna and malignant melanoma. A definite cytotoxic effect in cultures of malignant melanocytes was also reported. In order to establish if the cytotoxic effect of the diacid is exerted equally in the absence of tyrosinase, lymphoma- and leukemia-derived cell lines were cultured for 72 hr with 10(-3) M, 10(-2) M and 5 X 10(-2) M C9 disodium salt. Normal resting lymphocytes, lymphocytes activated by phytohemoagglutinin, and mouse Balb/c 3T3 fibroblasts were also tested to study a possible effect of azelaic acid on DNA synthesis and cell duplication. At 10(-3) M C9 had no effect on the viability of all the cells tested; at 10(-2) M and 5 X 10(-2) M, C9 2Na had a 50-80% cytotoxic effect on lymphoma- and leukemia-derived cell lines, while at the same concentrations it was not toxic to normal lymphocytes, either resting or stimulated, or to 3T3 fibroblasts. The experiments on cellular incorporation of (1-9 14C) azelaic acid showed that the radiocarbon uptake was two to three times higher for lymphoma- and leukemia-derived cell lines than for lymphocytes, either resting or stimulated, or 3T3 fibroblasts. Biochemical analysis revealed that the diacid underwent beta-oxidation in all the cell cultures. Fractionated centrifugations of 3T3 fibroblasts cultured in the presence of radiolabelled azelaic acid (2 X 10(-4) M) plus cold C9 2Na (10(-2) M), showed that the radioactivity was mainly concentrated in the cytoplasm. The results, being similar to those obtained by adding azelaic acid to cultures of melanoma cells, suggest that the cytotoxic effect of azelaic acid may be due to interference with mitochondrial oxido-reductase enzymes, rather than with tyrosinase. The difference in reaction between lymphoma- and leukemia-derived cell lines and normal or stimulated lymphocytes, and 3T3 fibroblasts, could be explained on the basis of a different degree of permeability of the cell membrane, and/or to a possible different sensitivity of reaction of mitochondrial functions. A similar argument could be used to explain the absence of an effect of dicarboxylic acids upon normal as compared with hyperactive or malignant melanocytes in vivo.
...
PMID:Activity of azelaic acid on cultures of lymphoma- and leukemia-derived cell lines, normal resting and stimulated lymphocytes and 3T3 fibroblasts. 400 85

We assessed the antiproliferative effect of tumor necrosis factor alpha (TNF-alpha) and lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, alone and in combination, on two murine tumor cell lines. Recombinant TNF-alpha inhibited proliferation of murine MmB16 melanoma cells in a concentration-dependent fashion but stimulated growth of murine L1210 leukemia cells at 0.1 ng/ml concentration. Lovastatin inhibited proliferation both of murine MmB16 melanoma cells and of murine L1210 leukemia cells in a concentration-dependent fashion. In combination with tumor necrosis factor alpha lovastatin inhibited synergistically growth of both cell lines as assessed by isobologram analysis. Our data show that lovastatin, a cholesterol synthesis inhibitor, introduced to the clinic to treat hypercholesterolemia, used either as a single or in combination with TNF-alpha inhibits growth of MmB16 melanoma and L1210 leukemia cells.
...
PMID:Synergistic antiproliferative activity of tumor necrosis factor alpha (TNF-alpha) and lovastatin. 748 65

<< Previous 1 2 3 4 5 6 7 8 9 Next >>