Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mouse leukemia L1210 cells selected for resistance to deoxyadenosine contain ribonucleotide reductase that is not feedback inhibited by dATP. These deoxyadenosine-resistant cells (Y8) also do not express p53 protein but do have WAF1 and Gadd45 mRNA and protein. The Y8 cells show increased sensitivity to DNA damaging agents and kinase inhibitors. In these studies we show that in the presence of sodium salicylate (NaSal), the parental wild-type (WT) cells block in G2/M phase of the cell cycle while the Y8 cells show a marked increased in the G0/G1 population of cells. The Y8 cells are more sensitive to apoptosis induced by NaSal than the WT cells. NaSal treatment causes the induction of caspase-3-like activity in Y8 cells but no induction of caspase-3 activity in the WT cells. The caspase inhibitor, Ac-DEVD-CHO, decreased the percentage of Y8 cells in the early apoptotic fraction, but this decrease was reflected by an increase in the percent of cells in the late apoptotic/necrotic fraction. SB20358, a p38-MAP kinase inhibitor did not protect the Y8 cells from NaSal-induced apoptosis indicating that the p38-MAP kinase pathway was not involved in the NaSal-induced apoptotic pathway in the p53-independent Y8 cells.
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PMID:Increased sensitivity to sodium salicylate-induced apoptosis in drug-resistant leukemia L1210 cells. 1129 31

Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of B-CLL cells. Activation of B-CLL lysates with dATP results in the formation of an approximately 700 kDa caspase-activating apoptosome complex containing Apaf-1. We describe for the first time the formation of a similar approximately 700 kDa caspase-activating apoptosome complex in B-CLL cells induced to undergo apoptosis by proteasome inhibitors.
Leukemia 2001 Sep
PMID:Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. 1151 99

The adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cells in the presence of either 2'-deoxyadenosine (dAdo) or its analog adenine arabinoside (araA). The concentration of dCF required to induce apoptosis of monocytoid leukemia cells is much lower than that required for myeloid, erythroid, or lymphoma cells. dATP effectively induces caspase-3 activation in cytosol from monocytoid cells, but not in that from non-monocytoid cells, suggesting that dATP-dependent caspase-3 activation is involved in the preferential induction of apoptosis in monocytoid leukemia cells. Athymic nude mice inoculated with human monocytoid leukemia U937 cells show significantly prolonged survival following combined treatment with dCF and araA. The clinical usefulness of the combination of adenosine deaminase inhibitor and dAdo analog is discussed.
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PMID:A novel therapeutic strategy against monocytic leukemia with deoxyadenosine analogs and adenosine deaminase inhibitors. 1169 50

The effects of 2-chloro-2'-deoxyadenosine (CdA, cladribine), an adenosine deaminase-resistant analogue toxic for both proliferating and resting lymphoid cells, were investigated in the human leukemia cell line EHEB, which was derived from a patient with B-cell chronic lymphocytic leukemia. These cells were found to be less sensitive to CdA than B-cell chronic lymphocytic leukemia lymphocytes (approximately 25-fold) and other human lymphoblastic cell lines (10-1000-fold). Phosphorylation of CdA by deoxycytidine kinase and intracellular accumulation of 2-chloro-2'-deoxyadenosine triphosphate (CdATP) were similar in EHEB cells and in other CdA-sensitive cell lines. In contrast, the inhibitory effect of CdA on ribonucleotide reductase activity, which was investigated in situ by the conversion of cytidine into deoxyribonucleotides and its incorporation into DNA, was much less pronounced in EHEB cells than in other human lymphoblastic cells. Accordingly, concentrations of deoxynucleoside triphosphates did not decrease and even tended to rise. Unexpectedly, incorporation of thymidine and deoxycytidine into DNA was increased severalfold after a 24-h incubation with CdA. CdA also increased the activities of deoxycytidine kinase and thymidine kinase approximately 4-fold. Analysis of the cell cycle by flow cytometry showed that after 24 h, CdA provoked an increase in the proportion of cells in S phase, synthesizing DNA. We conclude that the EHEB cell line is resistant to the cytotoxic action of CdA not only because of a lack of inhibition of ribonucleotide reduction but also because CdA, in contrast with its known effects, provokes in this cell line an increase in the proportion of cells replicating their DNA. Unraveling of the mechanism of this effect may shed light on clinical resistance to CdA.
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PMID:Resistance to 2-chloro-2'-deoxyadenosine of the human B-cell leukemia cell line EHEB. 1170 77

We previously reported that the aminopeptidase inhibitor bestatin induced apoptosis in several human leukemia cell lines. The present study was performed to examine whether bestatin can also induce apoptosis in solid tumor cell lines. Bestatin alone exhibited neither direct growth inhibition nor induction of apoptosis in the tumor cell lines examined. However, it significantly augmented the growth-inhibitory effect and induction of apoptosis by agonistic anti-Fas antibody (CH11). The augmentation by bestatin was also observed with other death ligands including tumor necrosis factor-alpha (TNF-alpha) in EBC-1 cells, a cell line sensitive to these death ligands. However, the HeLa S3 cell line, which is insensitive to TNF-alpha, showed no growth inhibition even by combination treatment. Bestatin methyl ester, a more cell-permeable derivative of bestatin with similar inhibitory activity to cytosolic neutral aminopeptidase, potentiated cell growth inhibition of CH11 more efficiently than bestatin. Other cytosolic neutral aminopeptidase inhibitors such as actinonin and puromycin also augmented cell growth suppression by CH11, while an enantiomer of bestatin lacking aminopeptidase inhibitory action did not increase the growth-inhibitory effects of CH11. The combination of 10 microg/ml of bestatin with CH11 promoted processing of caspase 3 to the active form p17 and efflux of mitochondrial cytochrome c into the cytosol more quickly and more intensely than CH11 alone. Inhibition of aminopeptidase was not involved in dATP- and cytochrome c-dependent caspase 3-activation in a cell-free system. Bestatin significantly augmented activation of caspase 8, which is upstream of cytochrome c efflux in the apoptosis cascade. These results suggested that intracellular neutral aminopeptidase might play an important role in Fas- or TNF-alpha-induced solid tumor cell apoptosis.
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PMID:Augmentation of death ligand-induced apoptosis by aminopeptidase inhibitors in human solid tumor cell lines. 1174 33

The purine nucleoside 2-chlorodeoxyadenosine (CdA) is often used in leukemia therapy. Its efficacy, however, is compromised by the emergence of resistant cells. In the present study, 3 CdA-resistant cell lines were generated and characterized. Their ability to accumulate 2-chloroadenosine triphosphate (CdATP) varied, reflecting differences in activities of deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK). Nonetheless, the selected lines were uniformly resistant to CdA-induced apoptosis, as assessed by caspase activation and DNA fragmentation. In contrast, cytosols from resistant cells were capable of robust caspase activation when incubated in the presence of cytochrome c and dATP. Moreover, replacement of dATP with CdATP also resulted in caspase activation in the parental and some of the resistant cell lines. Strikingly, CdA-induced decreases in mitochondrial transmembrane potential and release of cytochrome c from mitochondria were observed in the parental cells but not in any resistant lines. The lack of cytochrome c release correlated with an increased ability of mitochondria from resistant cells to sequester free Ca2+. Consistent with this enhanced Ca2+ buffering capacity, an early increase in cytosolic Ca2+ after CdA treatment of parental cells but not resistant cells was detected. Furthermore, CdA-resistant cells were selectively cross-resistant to thapsigargin but not to staurosporine- or Fas-induced apoptosis. In addition, CdA-induced caspase-3 activation and DNA fragmentation were inhibited by the Ca2+ chelator BAPTA-AM in sensitive cells. Taken together, the data indicate that the mechanism of resistance to CdA may be dictated by changes in Ca2+-sensitive mitochondrial events.
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PMID:Resistance of leukemic cells to 2-chlorodeoxyadenosine is due to a lack of calcium-dependent cytochrome c release. 1178 Dec 51

In a phase I study, 24 patients with refractory leukemia received Triapine, a novel ribonucleotide reductase (RR) inhibitor, as a continuous intravenous infusion over 96 h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120 mg/m(2) per day, and the maximum tolerated dose (MTD) was 160 mg/m(2) per day. Three of eight patients receiving 160 mg/m(2) per day in the first course, and one patient escalated to this dose in a second course, developed hepatic dose-limiting toxicity (DLT). For the days 1 and 8 regimen, the first 96 h infusion was administered at a fixed dose of 140 mg/m(2) per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160 mg/m(2) per day without observing DLT. No objective responses occurred. Over 70% of patients had a >50% reduction in white blood cell counts. The steady-state levels of Triapine were between 0.6 and 1 microM. As expected from the in vitro studies, at these plasma concentrations there was a decline in dATP and dGTP pools and a decrease in DNA synthetic capacity of the circulating leukemia cells. Based on these clinical, pharmacokinetic, and pharmacodynamic data, Triapine warrants further study in patients with hematologic malignancies.
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PMID:Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. 1292 43

The high fidelity of DNA replication is largely dependent upon accurate incorporation of dNTPs by DNA polymerases. To study the mechanism underlying nucleotide selection, we synthesized four nucleotide analogues bearing the unnatural bases benzimidazole, 5-nitrobenzimidazole, 6-nitrobenzimidazole, and 5-nitroindole and analyzed their incorporation by three DNA polymerases. We have found that human DNA polymerase alpha (pol alpha) and the Klenow fragment of Escherichia coli DNA polymerase I (KF) incorporate all four nucleotide analogues opposite all four canonical bases up to 4000-fold more efficiently than an incorrect natural dNTP (i.e., rates that approach those of a correct, natural dNTP), even though the shape of any base pair formed between the analogue and the template likely does not resemble a normal base pair. While pol alpha preferentially incorporated the analogues opposite template pyrimidines, KF surprisingly preferred to polymerize them opposite template purines. Although neither pol alpha nor KF readily polymerized a natural dNTP opposite either 5- or 6-nitrobenzimidazole in the template strand, the enzymes did incorporate the analogues to generate novel base pairs. Both pol alpha and KF polymerized the analogues up to 140-fold more efficiently than dATP both across from abasic sites and as 3'-overhangs on blunt-ended templates. Although Maloney murine leukemia virus reverse transcriptase did not measurably incorporate the analogues, this enzyme bound the analogues with K(I)'s only slightly higher than the K(m) for polymerization of the normal dNTP. The implications of these results with respect to how polymerases discriminate between correct and incorrect dNTPs are discussed.
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PMID:Facile polymerization of dNTPs bearing unnatural base analogues by DNA polymerase alpha and Klenow fragment (DNA polymerase I). 1295 Jan 74

2-Chloro-2'-deoxyadenosine (CldAdo, cladribine) is used therapeutically for hairy cell and other leukemias. The nucleoside is converted in leukemia cells to the 2-Cl-analog of dATP and incorporated into DNA, where it may alter binding of transcription factors to gene regulatory AT-rich sequences. Here we model the effects of CldATP incorporation into the adenovirus major late promoter TATA element recognized by TATA binding protein (TBP). The modeling results are consistent with experimental studies of DNA:TBP binding and indicate which positions in the canonical TATA sequence are most severely affected by CldATP incorporation.FIGURE Structure of the DNA:TBP complex. The protein is shown as a ribbon structure, and the DNA as a stick model
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PMID:2-Chloro-2'-deoxyadenosine: alteration of DNA:TATA element binding protein (TBP) interactions. 1461 Jun 62

Amidox, a new polyhydroxy-substituted benzoic acid derivative, is a potent inhibitor of the enzyme ribonucleotide reductase (RR), which catalyses the de novo synthesis of DNA. RR is considered to be an excellent target for anti cancer chemotherapy. We investigated the biochemical and antineoplastic effects of amidox as a single agent and in combination with Ara-C in human HL-60 promyelocytic leukemia cells. Amidox inhibited the growth of HL-60 cells in a growth inhibition assay with an IC50 of 25 microM. In a soft agar colony forming assay, amidox yielded a 50% inhibition of colony formation at 13 microM. We also investigated the effects of amidox treatment on the formation of deoxynucleosidetriphosphates. Amidox (50 and 75 microM for 24 hours) could significantly decrease intracellular concentrations of dCTP, dATP and dGTP pools, whereas dTTP levels increased. We then tested the combination effects of amidox with Ara-C; this combination yielded additive cytotoxic effects both in growth inhibition and in soft agar colony formation assays. This effect was due to the increased formation of Ara-CTP, the active metabolite of Ara-C, after preincubation with amidox. Preincubation of HL-60 cells with 75 and 100 microM amidox for 24 hours caused an increase in the intracellular Ara-CTP concentrations by 576% and 1143%, respectively. Therefore amidox might offer an additional option for the treatment of leukemia and thus be further investigated in in vivo studies as a single agent and in combination with Ara-C.
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PMID:Biochemical modulation of Ara-C effects by amidox, an inhibitor of ribonucleotide reductase in HL-60 promyelocytic human leukemia cells. 1468 48


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