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)

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +/- 300.4 nM x h at Level 1 (n = 3) to 3411.3 +/- 341.0 nM x h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.
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PMID:Phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies. Cladribine Study Group. 925 68

2-Chlorodeoxyadenosine (2-CdA) is a purine nucleoside analogue with therapeutic activity in low-grade lymphoproliferative disorders. In addition, 2-CdA has a potent myelosuppressive effect, and it has been shown to be toxic to malignant myeloid cells both in vitro and in vivo. In this pilot study we treated nine patients who had advanced myelofibrosis with myeloid metaplasia (MMM) and progressive hepatomegaly or symptomatic thrombocytosis after therapeutic splenectomy. 2-CdA was administered at 0.05-0.1 mg/kg/d for 7 d for one to five treatment cycles. A reduction in liver size associated with marked improvement in fatigue and control of thrombocytosis and leucocytosis was achieved in seven of the nine patients (78% response rate). In four of the seven responding patients the reduction in liver size was durable (4-28 months) and was associated with a decrease in serum alkaline phosphatase levels. However, no patient had improvement in anaemia, and two of the seven initially responding patients have since died of acute leukaemia or progressive disease. Improvement in bone marrow fibrosis was noted in two of five available post-treatment marrow examinations. Toxicity was mainly myelosuppression, which was severe in two patients. 2-CdA may be considered a palliative therapeutic agent after splenectomy in noncytopenic patients with MMM who have progressive hepatomegaly or extreme thrombocytosis.
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PMID:2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. 969 87

Mouse leukemia L1210 cells were generated for resistance to deoxyguanosine by two different methods. In one case the L1210 cells were subjected to gradual increases in deoxyguanosine (dGuo-R); in the second approach, the cells were subjected to deoxyguanosine at a concentration ten times the IC50 value and plated out on soft agar (D-92). The dGuo-R and D-92 cell lines had different phenotypic expressions. The dGuo-R cells showed a higher degree of resistance to dGuo than the D-92 cells. The levels of resistance to other cytotoxic drugs such as araC or 2-chloro-2'-deoxyadenosine did not necessarily correlate with the degree of resistance to dGuo. Deoxycytidine kinase activity was decreased in both of the cell lines, although there was a larger decrease in the dGuo-R cell line. The levels of kinase activities toward the other substrates were not all coordinately decreased in these cell lines. The degree of resistance of these cell lines to dGuo cannot be ascribed solely to an alteration at the deoxycytidine kinase site.
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PMID:Alterations in the properties of mouse leukemia L1210 cell lines selected by different methods for resistance to deoxyguanosine. 938 77

Thermus aquaticus (Taq) DNA polymerase elongation is blocked by several DNA adducts. This property has been exploited in polymerase chain reaction (PCR) methods to analyze cellular DNA damage and repair after exposure to damaging agents. Such methods have not been applied previously to detect nucleoside analog incorporation into cellular DNA. 2-Chloro-2'-deoxyadenosine (CldAdo), a deoxyadenosine analog, is clinically effective for hairy cell leukemia. CldAdo is taken up by cells, converted to the triphosphate, and incorporated into cellular DNA. Here, we measured by primer extension the ability of CldAMP residues in 98-base single-stranded DNA to block Taq elongation. In contrast to control DNA, no full-length 98-mers were produced on CldAMP-containing templates, and Taq polymerase was halted at the first CldAMP site. We then examined the possibility of using quantitative PCR to measure CldATP incorporation into the N-ras gene after incubation of cultured human leukemia cells with CldAdo or with cisplatin as a positive control for DNA damage. Treatment with either drug resulted in reduced amounts of amplified DNA product compared to untreated cells. CldAMP residues within cellular DNA inhibited PCR amplification in a dose-dependent manner; 100 nM CldAdo produced approximately 0.4 CldAMP sites within a 523-bp region of the N-ras sequence. Thus, PCR analysis with Taq polymerase provides a sensitive assessment of nucleoside analog incorporation after cellular exposure to antileukemic drugs.
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PMID:Analysis of 2-chloro-2'-deoxyadenosine incorporation into cellular DNA by quantitative polymerase chain reaction. 973 41

The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2'-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia.
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PMID:Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2'-deoxycoformycin and 2'-deoxyadenosine: association with dATP-dependent activation of caspase-3. 978 75

2-Chloro-2'-deoxyadenosine (CdA) is a new purine nucleoside analogue with major activity in lymphoproliferative diseases. Its intracellular nucleotides, in particular the 5'-triphosphate, are thought to be the pharmacologically active metabolites. The present study was undertaken to elucidate the cellular pharmacokinetics of these active metabolites in leukemia patients during CdA treatment. The concentrations of CdA in plasma and of CdA nucleotides (CdAN) in leukemic cells were measured by liquid chromatography in 69 patients with chronic lymphocytic, acute myeloid, and hairy cell leukemia after intermittent and continuous i.v. infusion, s.c. injection, and p.o. administration. The t1/2 of CdAN during the first dose interval was 13.8 h (n = 67), while after the last dose the t1/2 was 32.7 h (n =8). The area under the concentration versus time curve was similar after intermittent and continuous infusion, 268.3 and 237.8 &mgr;m/h, respectively (n = 7). The area under the concentration versus time curve after p.o. administration (0.24 mg/kg) was slightly lower than that after intermittent infusion (0.12 mg/kg), 120.6 versus 188.8 &mgr;m/h (P < 0.05, n = 7). However, when all p.o. administrations (n = 16) were compared with all 2-h infusions in other patients with chronic lymphocytic leukemia (n = 32), there was no significant difference (149.6 versus 168.6 &mgr;m/h). The cellular concentration of CdAN was 320 times higher than the plasma concentration of CdA, but there was no correlation in individual patients (r2 = 0.02, n =69). The t1/2 of CdAN was significantly shorter in patients with acute leukemias (9 h) compared to those with chronic lymphocytic (12.9 h) and hairy cell leukemias (15.1 h). The area under the concentration versus time curve of CdAN in leukemic cells from the 11 patients with hairy cell leukemia given CdA s.c. was in the same range (179.8 &mgr;m/h) as in patients with chronic lymphocytic leukemia. The retention of CdAN in leukemic cells supports intermittent administration. The lack of correlation between cellular and plasma drug concentrations indicates that plasma drug concentrations are not useful for individualization of dose.
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PMID:Cellular pharmacokinetics of 2-chloro-2'-deoxyadenosine nucleotides: comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients 981 95

2-Chloro-2'-deoxyadenosine, (CldAdo) resistance was developed in the W1L2 human B lymphoblastoid (resistance factor, 160) and L1210 murine leukemia (resistance factor, 605) cell lines by continuous exposure to CldAdo. Cross-resistance studies showed that while the variant lines generally retained sensitivities to 9-beta-D-arabinofuranosyladenine (in the presence of 2'-deoxycoformycin), hydroxyurea, and Adriamycin, both were highly cross-resistant to 1-beta-D-arabinofuranosylcytosine (ara-C), 2', 2'-difluorodeoxycytidine, and 9-beta-D-arabinofuranosyl-2-fluoroadenine. Measurement of both phosphorylating and degrading enzyme activities demonstrated that initial phosphorylation of CldAdo and 2'-deoxycytidine were severely impaired in cell extracts from the resistant lines, whereas adenosine kinase activity remained unaffected and there was no apparent increase in cytoplasmic deoxynucleotidase activity using dCMP as substrate. Since previous reports indicated that either overexpression of Bcl-2 protein following bcl-2 transfection into cells resulted in, or high dCTP pools contributed to, ara-C resistance in experimental cell models, both of these parameters were assessed and found not to contribute to CldAdo resistance in the murine leukemia and human B lymphoblastoid cells. These studies show that a deficiency of 2'-deoxycytidine kinase activity is a major determinant of CldAdo acquired resistance in both the murine and human lymphoid lines.
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PMID:2'-Deoxycytidine kinase deficiency is a major determinant of 2-chloro-2'-deoxyadenosine resistance in lymphoid cell lines 981 96

S-Adenosylmethionine (AdoMet) synthetase (EC 2.5.1.6), which catalyzes the synthesis of AdoMet from methionine and ATP, is the major methyl donor for transmethylation reactions and propylamino donor for the biosynthesis of polyamines in biological systems. We have reported previously that wild-type C-1300 murine neuroblastoma (wMNB) cells, made resistant to the nucleoside analogue (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842), an irreversible inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1), express increased AdoMet synthetase activity (M. R. Hamre et al., Oncol. Res., 7: 487-492, 1995). In the present study, immunoblot analyses of AdoMet Synthetase with isoform-specific (MATII) antibodies demonstrated an elevation in the AdoMet synthetase immunoprotein in nucleoside analogue-resistant MNB cells (rMNB-MDL) when compared to wild-type, nonresistant MNB cells. An increase of 2.1-fold was observed in the alpha2/alpha2' catalytic subunit, which differed significantly from the much smaller increment in the noncatalytic beta-subunit of AdoMet synthetase. Densitometric analyses revealed that an increased expression of AdoMet synthetase in rMNB-MDL cells was due to overexpression of the alpha2 (Mr 53,000; 2.6-fold) and alpha2' (Mr 51,000; 1.8-fold) subunits. AdoMet synthetase mRNA expression in rMNB-MDL cells was remarkably greater than wMNB cells, as determined by quantitative competitive reverse transcription-PCR (QC-PCR) analysis. DNA (cytosine) methyl transferase expression, measured by reverse transcription-PCR analysis, was also elevated significantly in rMNB-MDL cells. In contrast, Western blot analyses demonstrated down-regulation (1.6-fold) of AdoMet synthetase in doxorubicin-resistant human leukemia cells (HL-60-R) expressing multidrug resistance protein when compared with wild-type, nonresistant HL-60 cells. The resistance of rMNB-MDL cells to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase correlates directly with overexpression of the alpha2/alpha2' subunits of AdoMet synthetase. Cellular adaptation allows sufficient AdoMet to be synthesized, so that viability of the MNB cells can be maintained even in the presence of high AdoHcy concentrations. This novel mechanism of drug resistance does not appear to require multidrug resistance protein (P-glycoprotein) overexpression.
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PMID:S-adenosylmethionine synthetase is overexpressed in murine neuroblastoma cells resistant to nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase: a novel mechanism of drug resistance. 1021 91

Because 2-chloro-2'-deoxyadenosine (CdA) is active in B-chronic lymphocytic leukemia (B-CLL), and may interfere with DNA repair, we investigated the potentiating effect of CdA on the cytotoxicity induced in vitro in B-CLL lymphocytes by cyclophosphamide (CP) derivatives, which induce DNA damage by DNA cross-linking. Exposure to CdA at clinically achievable concentrations for 2 h, followed by mafosfamide (MAF) or 4-hydroxycyclophosphamide (4HC) for 22 h, resulted in synergistic cytotoxicity in the majority of B-CLL samples tested. Synergy between CdA and MAF was observed in cell samples of sensitive/untreated patients, as well as in cells of resistant/pretreated patients, particularly at the highest concentrations of MAF. In the cells treated with CdA and MAF, we observed loss in ATP and hallmarks of apoptosis, as evidenced by cellular morphology and high molecular weight DNA fragmentation. The synergy could be explained neither by an influence of MAF on the phosphorylation of CdA, nor by an increase in the incorporation of CdA into DNA in the presence of MAF. The in vitro synergy between CdA and CP derivatives provides a rationale for the use of this association in B-CLL patients.
Leukemia 1999 Jun
PMID:Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic lymphocytic leukemia cells by 2-chloro-2'-deoxyadenosine. 1036 Mar 81

The nucleoside analogue cordycepin (3'-deoxyadenosine, 3'-dA) is substantially more cytotoxic to terminal deoxynucleotidyl transferase positive (TdT+) leukemic cells than to TdT leukemic cells in vitro in the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), and has been considered as a therapeutic agent for TdT+ leukemia. The intracellular metabolism of 3'-dA was examined with HPLC, and the mechanism of its anti-TdT+ leukemic activity was analyzed. In the presence of dCF (2.5 microM), TdT+ leukemic cells (N = 5) were sensitive to the cytotoxic effect of 3'-dA, whereas TdT (N = 6) cells were not. A high level of 3'-dA-5'-triphosphate (3'-dATP) formation was detected in TdT+ NALM-6 cells (67 pmol/10(6) cells) and TdT- K562 cells (49 pmol/10(6) cells) when cultured with 1 microM [3'-3H]-labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT HUT-102 cells (27 pmol/10(6) cells), whereas the level of 3'-dATP in TdT+ MOLT-4 cells was low (0.3 pmol/10(6) cells). The mean IC50 values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 microM, respectively. There was a modest level of 3'-dATP (7 pmol/10(6) cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/10(6) cells). These data suggest that the presence of 3'-dATP is not sufficient for the antileukemic effect of 3'-dA, but that TdT positivity is essential, and that PBM are significantly less sensitive to the cytotoxicity of 3'-dA in vitro. Further development of 3'-dA as a potential antileukemic agent to treat patients with TdT+ leukemia is warranted.
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PMID:Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells. 1060 56


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