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)

The promyelocytic leukaemia cell line HL-60 differentiates to a macrophage-like cell when exposed to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and other agents which activate protein kinase C. To investigate this phenomenon we developed an HL-60 variant which does not differentiate when exposed to TPA. HL-60 cells were exposed to the mutagen ethyl methanesulphonate and were cloned in soft agar in the presence of a normally lethal concentration of TPA. One colony of cells that proliferated in TPA was obtained. The cells of this phorbol ester tolerant (PET) line have retained their resistance to TPA for several years without selective pressure. They are somewhat larger than their phorbol ester sensitive (S) parent, but they are otherwise morphologically similar. When PET-cells are exposed to TPA their growth is arrested for approximately 48 h. Thereafter, they resume their original rate of replication at all concentrations of TPA tested. S-cells undergo changes typical of HL-60 when exposed to TPA; they aggregate, stop growing, adhere to the flask and die. The PET-cells appeared to be as sensitive as S-cells to other agents which differentiate HL-60 such as retinoic acid, dimethysulphoxide, and 1,25-dihydroxyvitamin D3, as determined by rate of proliferation in culture, Wright's stain, nitroblue tetrazolium reduction, and induction of the ectoenzyme NAD-glycohydrolase. TPA-induced protein phosphorylation was studied using one- and two-dimensional polyacrylamide gel electrophoresis. Several proteins increased their incorporation of 32P when S- and PET-cells were exposed to TPA, the most prominent of which were the two previously described nuclear matrix proteins of 80 kd and 33 kd. There was no difference in the protein phosphorylation pattern in S- and PET-cells, nor in how this pattern changed on TPA exposure. Fluorescent activated cell sorting and karyotypic analysis revealed PET-cells to be a hypotetraploid variant of S-cells, with approximately 80 chromosomes, including a marker chromosome iso(1p) not found in the S-cells. Identification of the biochemical lesion responsible for this TPA resistance in PET cells will provide clues concerning the mechanism of this important pathway for the induction of cell differentiation.
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PMID:A phorbol ester tolerant (PET) variant of HL-60 promyelocytes. 316 84

The adenine nucleotide profiles (AMP, ATP, NAD and NADH2) of peripheral blood lymphocytes isolated from patients with common variable hypogammaglobulinaemia (CVH) were similar to those in control cells. AMP and ATP levels were also similar in the lymphocytes of patients with chronic lymphatic leukaemia (CLL). Since CVH and CLL patients have reduced activity of plasma membrane ecto-5'-nucleotidase, our data suggests that this enzyme does not regulate the levels of intracellular adenine nucleotides, at least in "resting" cells.
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PMID:Adenine nucleotide concentrations in peripheral blood lymphocytes from patients with common variable hypogammaglobulinaemia and B-cell chronic lymphatic leukaemia. 318 62

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.
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PMID:Metabolism of prostaglandin E2 by human HL-60 leukemia cells. 347 88

The purpose of this investigation was to examine factors which regulate the reprogramming of gene expression in tumors responsible for resistance to tiazofurin. To study the resistance phenomenon drug-induced tumor lines were selected and examined for the mechanism of resistance. A comparison of the biochemical expression of resistance to tiazofurin in drug-induced resistant lines of hepatoma 3924A, leukemias L1210 and P388 revealed that the 3 lines expressed similar genetic alterations related to reduced TAD content, decreased NAD pyrophosphorylase activity and increased synthesis of guanylates from salvaging preformed guanine indicating that these 3 factors play an important role in the resistance to tiazofurin. Resistance was stable in the leukemia lines and did not require drug to maintain resistance. Hepatoma 3924A resistant line reverted to sensitive state in the absence of drug selection pressure. NAD pyrophosphorylase activity was substantially deleted in the tiazofurin resistant leukemia lines, but was only significantly decreased in the hepatoma resistant line. Extensive biochemical alterations including enhanced activity of IMP dehydrogenase, increased inosinate and guanylate pools, and reduced uptake of tiazofurin were found in the hepatoma line resistant to tiazofurin. To examine the applicability of these results to naturally sensitive and spontaneously resistant tumors, murine tumors were examined. In murine tumors, TAD accumulation, ratios of enzyme activities responsible for the synthesis and degradation of TAD, and the ratios of perturbation of inosinate and guanylate pools following tiazofurin challenge demonstrated significant correlation with the sensitive or resistant nature of the tumors. To extrapolate these observations to human tumor systems, cytotoxicity of tiazofurin and its metabolic effects were compared in 6 human lung cancer cell lines derived from cancer patients with small cell lung cancer (4 lines) and lung adenocarcinoma (2 lines). Cell lines exhibiting greater sensitivity to tiazofurin accumulated significantly larger amounts of TAD and showed significant reduction of guanylate pools following tiazofurin incubation. The activity of the enzyme responsible for the formation of TAD, NAD pyrophosphorylase, did not correlate with responsiveness to tiazofurin but the enzyme which hydrolyzes TAD, TADase, correlated positively with the status of resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical mechanisms of resistance to tiazofurin. 383 25

Following the parenteral administration of tiazofurin, 2-beta D-ribofuranosylthiazole-4-carboxamide (thiazole nucleoside, TR), a potent but reversible inhibitor of IMP dehydrogenase is generated in subcutaneous nodules of the P388 leukemia. The compound responsible for this effect has been isolated from homogenates of the tumor by ion-exchange HPLC, and its presence monitored by enzyme-inhibition assay. The inhibitor has also been prepared by incubation of tiazofurin with P388 cells in culture. Chromatographically, the inhibitory principle exhibits a moderately strong set negative charge at pH 3, and elutes in the general vicinity of the nucleoside-5'-diphosphates; its absorption maximum in aqueous solution (pH 7) lies at 252 nm. Exposure of the molecule to snake-venom phosphodiesterase or to nucleotide pyrophosphatase destroys its inhibitory potency, whereas other phosphodiesterases are either less effective or inert. Since these results suggested that the anabolite might be a dinucleotide with a phosphodiester linkage of the kind found in NAD, attempts were made to synthesize such an analogue from the 5'-monophosphate of thiazole nucleoside and ATP-Mg2+, using a purified preparation of NAD pyrophosphorylase; modest yields were obtained of a compound with chromatographic, spectral and enzyme-inhibitory properties identical to those of the material isolated from P388 tumor nodules. This enzyme-synthesized material was radioactive when [3H]ATP was used as cosubstrate, and yielded both AMP and thiazole nucleoside-5'-monophosphate on treatment with phosphodiesterase. It resisted attack by NAD glycohydrolase. An apparently identical dinucleotide was also synthesized chemically by means of the Khorana condensation. Mass spectral analysis and nuclear magnetic resonance studies with homogeneous preparations of both the enzymically and chemically synthesized compound were compatible with its being a dinucleotide in which the nicotinamide of NAD has been replaced by thiazole-4-carboxamide. Versus IMP dehydrogenase, the dinucleotide exhibited a K1 of approximately 2 X 10(-7) M and was non-competitive with NAD as the variable substrate. Other NAD utilizing enzymes, including representative dehydrogenases and poly ADP ribose polymerase, were, by comparison to mammalian IMPD, resistant to inhibition by TAD. The properties of this novel dinucleotide are compared and contrasted with those of analogs of NAD containing modifications in the pyridine, adenine or ribofuranose rings, as well as in the pyrophosphate bridge.
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PMID:Studies on the mechanism of action of tiazofurin metabolism to an analog of NAD with potent IMP dehydrogenase-inhibitory activity. 615 29

Immunologic and cytochemical studies were done in 162 patients with myeloid forms of acute leukosis, among whom 130 had acute myeloblastic leukemia (AML), and thirty two--and acute myelomonoblastic leukemia (AMML), before and after the therapy instituted. Immunocorrection was attempted with immunomodulating agents prodigiosane and tactivin. Striking inhibition of T-cellular immunity (T-total, T-active, TPhres, TPhsen, as well as blast transformation of lymphocytes with PHA) was revealed. All patients experienced significant rise in circulating immune complexes before treatment. Investigation designed to study intracellular metabolism of neutrophils demonstrated significant decline in the activities of G-6-P-ase, NAD- and NADP-oxidases, cationic proteins and NBT-test. Immunocorrective agents improve the state of immunologic reactivity, make for arresting infections and inflammatory processes and prolongation of remission in patients with acute myeloid forms of leukoses.
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PMID:[Immunological deficiency in patients with the myeloid forms of acute leukemia and the methods for its correction]. 760 94

Tiazofurin exhibits antitumor activity in murine and human tumor cells. In a recent phase I/II trial in patients with end-stage leukemia, tiazofurin showed good response; however, repeated treatment resulted in clinical resistance to the drug. To elucidate the mechanisms of resistance in human leukemic cells, two variants of human myelogenous leukemia K652 cells resistant to tiazofurin were developed by drug-selection pressure. Compared to a concentration producing 50% cell proliferation reduction that was 9.1 microM in sensitive cells, the resistant variants displayed concentrations producing 50% cell proliferation reductions of 12 and 16 mM. The activity of the target enzyme, IMP dehydrogenase, was not altered in the resistant cells. Studies on tiazofurin metabolism revealed that resistant variants formed < 10% of the active metabolite, thiazole-4-carboxamide adenine dinucleotide. This correlated with the activity of NAD pyrophosphorylase, the enzyme that synthesizes thiazole-4-carboxamide adenine dinucleotide, which was reduced to 10% in the resistant lines. Concurrently, the activity of thiazole-4-carboxamide adenine dinucleotide phosphodiesterase was elevated in the refractory cells. Compared to the sensitive counterpart, the levels of GMP and NAD were lower in the resistant lines. Guanine salvage activity was decreased in the resistant cells. Basal dGTP and dATP concentrations were elevated in the resistant line; nevertheless, tiazofurin incubation decreased dGTP levels in only the sensitive cells. Although there was no difference in the Km of tiazofurin transport or efflux, the Vmax of uptake of the drug was reduced in the resistant lines. Sensitive and resistant cells exhibit similar cytotoxicity to agents which do not share the mechanism of action of tiazofurin, suggesting that refractory cells are still sensitive to other standard antileukemic drugs.
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PMID:Biochemical consequences of resistance to tiazofurin in human myelogenous leukemic K562 cells. 809 64

The metabolism of purine nucleotides was studied in human peripheral blood lymphocytes from healthy subjects and patients with B-cell chronic lymphocytic leukemia. Nucleotide content was determined by HPLC. The rate of de novo synthesis of purine nucleotides was measured kinetically by following the incorporation of 14C-formate into the nucleotides of a lymphocyte suspension. The patterns of the main enzymes involved in purine nucleotide metabolism (those of the salvage pathway and catabolism) were estimated by a radiochemical method. Although the data expressed in relation to cells and protein showed some discrepancies, several common differences were evident in both cases. The main differences were an increase in NAD and IMP, a sharp decrease in 5'-nucleotidase activities and in total guanylate content and synthesis, and an increase in the A/G ratio in lymphocytes of patients with respect to controls. The changes in these parameters in CLL indicate an imbalance in purine metabolism and may play a specific role in the biology of the leukemia cell. They are also potential biochemical markers of lymphoid malignancies and may be useful in chemotherapic applications.
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PMID:Purine nucleotide metabolism: specific aspects in chronic lymphocytic leukemia lymphocytes. 919 62

Benzamide riboside (BR) exhibits potent antitumor activity in a variety of cultured human tumor cells. The drug is metabolized to benzamide adenine dinucleotide (BAD), which in turn functions as a selective inhibitor of IMP dehydrogenase (IMPDH) activity with a Ki of 0.118 microM. In vitro, BR is a more potent antitumor inhibitor of IMPDH than tiazofurin, another IMPDH inhibitor which has shown significant oncolytic activity in adult patients with end-stage leukemia. To elucidate the mechanism of resistance, a variant of human myelogenous leukemia K562 cells was developed by subculturing sensitive cells in sublethal concentrations of BR over 60 generations. The BR resistant line that emerged exhibited an IC50 (a concentration producing 50% reduction in cell proliferation) of 148 microM, compared to the sensitive line which had an IC50 of 1.6 microM. The activity of the target enzyme, IMPDH, was increased 3-fold in the resistant variant. Studies on BR metabolism revealed that resistant cells formed only 18% of the active metabolite, BAD, compared to sensitive cells. This finding, in turn, correlated with the specific activity of NAD pyrophosphorylase (the enzyme responsible for the synthesis of BAD) which was reduced to undetectable levels in the resistant variant. The basal levels of NAD and guanylates were also significantly decreased to 41% and 48%, respectively, in the resistant line compared to the parent line. Additionally, after treatment with BR a decrease in guanylate level was observed only in the sensitive cells. Sensitive and resistant cells exhibit comparable cytotoxicity to agents outside the tiazofurin family, suggesting that a multidrug resistance was unlikely to explain the resistance to BR. Moreover, BR resistant cells exhibit collatoral sensitivity to 6-aminopurine, cytarabine and 5-fluorouracil, which have different mechanisms of action. In conclusion, these studies establish that the primary mechanism of resistance to BR involves an increase in IMPDH (target enzyme) activity with a concurrent decrease in NAD pyrophosphorylase (BAD synthetic enzyme) activity.
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PMID:Biochemical consequences of resistance to a recently discovered IMP dehydrogenase inhibitor, benzamide riboside, in human myelogenous leukemia K562 cells. 941 15

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.
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PMID:Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis. 1036 12


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