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 mode of transport of a nonphosphorylated adenosine analog, 5'-deoxyadenosine, was studied in murine leukemia L1210 cells. This compound is not subject to the action of intracellular nucleoside-trapping kinases, and its transport can be examined without regard for effects of experimental conditions on kinase activity. Accumulation of 5'-deoxyadenosine was rapid, and nonconcentrative, with equilibrium attained within 12 s at 37 degrees. Kinetic studies were carried out at 20 degrees. We found both a nonmediated (diffusion) and a mediated transport process. The latter had an apparent Km fo 115 micrometer, Vmax = 105 pmol/10(6) cells/min. Uptake of 5'-deoxyadenosine was inhibited by several heterologous nucleosides including adenosine, 2'-deoxyadenosine, thymine riboside, and inosine. Like 2'-deoxyadenosine, 5'-deoxyadenosine was more lipid-soluble than adenosine (from octanol/water partition studies). Compared with 5'-deoxyadenosine, adenosine had a much lower apparent Km (5 micrometer) and a higher Q10 over the 27-37 degrees range (3.0 versus 1.3). Data obtained with adenosine might, however, reflect properties of intracellular adenosine kinase interacting with a transport process.
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PMID:Transport of a nonphosphorylated nucleoside, 5'-deoxyadenosine, by murine leukemia L1210 cells. 20 33

2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum of activity may be attributable to the selective toxicity of CdA to nondividing lymphocytes and monocytes. However, CdA is unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. The present experiments demonstrate that the 2'-arabino-fluoro derivative of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted degradation by Escherichia coli nucleoside phosphorylase. Cell killing was preceded by the formation of DNA strand breaks and could be prevented by supplementation of the medium with deoxycytidine. The initial DNA damage initiated the pattern of oligonucleosomal DNA fragmentation characteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycytidine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotide reductase activity, were cross-resistant to both CAFdA and CdA toxicity. One-week oral treatment with CAFdA (1 mg/ml in drinking water) achieved an average plasma concentration of 0.56 microM and eliminated 90% of chronic lymphocytic leukemia cells transplanted into severe combined immunodeficiency (scid) mice. Under the same conditions, CdA was much less active. Collectively, these results suggest that CAFdA could be effective as an oral agent in indolent lymphoproliferative diseases and in autoimmune diseases where lymphocyte and monocyte depletion is desirable.
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PMID:Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. 134 62

Soluble Interleukin-2 Receptor (sIl-2R) and Tumor Necrosis Factor-alpha (TNF-alpha) have been found significantly increased in serum samples of patients with HCL at diagnosis and a strict correlation with leukemic burden has been reported. Furthermore, following therapy, serological monitoring of these cytokines may be considered a useful tool for controlling therapeutic efficacy and for detection of minimal residual disease. Eighteen HCL patients, treated with 2-Chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily for 7 days, entered the study all of them showing increased levels of sIL-2R and TNF-alpha prior to therapy. After therapy, serum levels were reassessed and a remarkable decrease was recorded in all cases. In particular, after 1 month by the end of treatment sIL-2R and TNF-alpha decreased from 3,377 +/- 2,303 to 149 +/- 96 pM/ml (p = 0.00003) and from 38 +/- 41 to 18 +/- 18 pg/ml (p = 0.015) respectively. The only 3 patients who did not normalize sIL-2R and TNF-alpha levels showed also an evident persistence of the disease in the marrow. In conclusion, 2-CdA leads to a rapid normalization of the increased levels of sIL-2R and TNF-alpha in the majority of HCL patients. Furthermore, monitoring of these cytokines represents a useful tool for detecting minimal residual disease.
Leukemia 1992 Nov
PMID:Biological markers and minimal residual disease in hairy cell leukemia. 135 4

The effects of inhibition of the capacity to form spermidine and spermine on cell growth were investigated using murine leukaemia L1210 cells and 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811, AbeAdo), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase. Putrescine levels were increased 80-fold, and spermidine and spermine levels were greatly reduced after a 3-day exposure to a maximally inhibitory dose of 10 microM-AbeAdo. Addition of AbeAdo to the culture medium inhibited the growth of L1210 cells measured 3 days later in a dose-dependent manner, but, even at a dose of 10 microM, which was maximally effective, exposure to AbeAdo was not immediately cytostatic. However, the growth rate of L1210 cells chronically exposed to 10 microM-AbeAdo declined steadily until day 12, when the cells stopped growing. L1210 cells exposed to AbeAdo for 12 days could not be rescued from cytostasis by removal of the drug from the culture, but could be rescued by exposure to exogenous spermidine or spermine, indicating that the growth-inhibitory effects of AbeAdo were a result of spermidine and/or spermine depletion. It is suggested that elevated intracellular putrescine in AbeAdo-treated cells sustained limited growth in the absence of physiological levels of spermidine and spermine until certain critical and specific physiological role(s) fulfilled by spermidine (and/or spermine) became deficient resulting in cytostasis. N-(3-Aminopropyl)-1,4-diamino-cis-but-2-ene, a spermidine analogue that is a substrate for deoxyhypusine synthase, was able to mimic the effects of spermidine in reversing AbeAdo-induced cytostasis. Spermidine analogues such as 5,5-dimethylspermidine, which are not substrates for deoxyhypusine synthase, were not active in this way. These results provide evidence that the formation of hypusine in the protein-synthesis initiation factor eIF-5A may be a critical role of spermidine essential for cell growth.
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PMID:Cytostasis induced in L1210 murine leukaemia cells by the S-adenosyl-L-methionine decarboxylase inhibitor 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine may be due to hypusine depletion. 144 35

An irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC), 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), was found to cure Trypanosoma brucei brucei and multidrug-resistant T. b. rhodesiense infections in mice [Bitonti, Byers, Bush, Casara, Bacchi, Clarkson, McCann & Sjoerdsma (1990) Antimicrob. Agents Chemother. 34, 1485-1490]. Doses of this drug which resulted in a rapid clearance of parasites from T. b. brucei-infected rats resulted in plasma levels of 50-60 microM-MDL 73811 and an intratrypanosomal MDL 73811 concentration of 1.9 mM within 10 min of administration [Byers, Bush, McCann & Bitonti (1991) Biochem. J. 274, 527-533[. Based on this finding we speculated that MDL 73811, which is an adenosine analogue, is a substrate for the trypanosome active purine transport system. We now report evidence that supports this hypothesis. MDL 73811 uptake by T. b. brucei in vitro was time- and temperature-dependent and was saturable over a time course in which MDL 73811 metabolism was undetectable, suggesting that MDL 73811 uptake is a transport-mediated phenomenon. Inhibition of MDL 73811 uptake by purine nucleosides is consistent with the drug being a substrate for the trypanosome purine transport system. The accumulation of MDL 73811 by cultured L1210 mouse leukaemia cells was significantly less than by trypanosomes exposed to the same pharmacologically relevant concentrations of MDL 73811. Given that the half-life of MDL 73811 in the plasma of rats and mice is approx. 10 min, it seems likely that the existence of a highly active parasite transport system for MDL 73811 is crucial for the sensitivity of trypanosomes towards MDL 73811 in vivo, and that the absence of active transport of MDL 73811 by the host's cells may play a role in the selectivity of this drug.
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PMID:Uptake of the antitrypanosomal drug 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811) by the purine transport system of Trypanosoma brucei brucei. 159 Jul 65

To evaluate its toxicity and clinical efficacy in children with relapsed or refractory leukemia, we performed a phase I trial of 2-chloro-2'-deoxy-adenosine (2-chlorodeoxyadenosine; 2-CDA) given as a continuous 5-day infusion at doses of 3 to 10.7 mg/m2/d. In this study of 31 children with acute leukemia, the only dose-limiting toxicity was myelosuppression. At the highest dose level, three of seven patients developed fatal systemic bacterial or fungal infections. At dose levels above 6.2 mg/m2/d, significant oncolytic responses occurred in all patients. In addition, there was a significant correlation between both the responsiveness by cell type and dose of 2-CDA, such that more oncolytic responses were noted in acute myeloid leukemia (AML) patients than acute lymphoblastic leukemia (ALL) patients (P = .02). Although this was a phase I trial in heavily pretreated patients with refractory disease, two AML patients treated at 5.2 and 10.7 mg/m2/d, respectively, had complete hematologic responses, and one patient treated at 10.7 mg/m2/d had a partial response. In addition, there was a dose-response relationship in all patients with improved cytoreduction of peripheral blast cells at higher doses of 2-CDA. In vitro evaluation of 2-CDA uptake and anabolism by leukemic blast cells from 22 patients demonstrated that 2-chloro-2'-deoxyadenosine (Cld-AMP) and 2-chloro-2'-deoxyadenosine 5'-striphosphate (CldATP) reached concentrations close to steady-state levels within 1 hour. Intracellular nucleotide disappearance rates were high with half-lives of 1.29 and 2.47 hours for CldAMP and CldATP, respectively. This suggests that continuous infusion is necessary to maintain the desired plasma concentration. The results of this study confirm the antileukemic activity of 2-CDA and the lack of prohibitive nonhematologic toxicity. Phase II trials in patients with AML and ALL are warranted.
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PMID:A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. 167 75

The first high performance liquid chromatographic method for determination of the plasma concentration of 2-chloro-2'-deoxyadenosine (CdA) in patients, which is significantly more sensitive than the previously used RIA method, is presented. CdA is a purine analogue with useful clinical activity against lymphoproliferative disorders and it has recently been found to be the single most active agent in the treatment of hairy cell leukaemia. Guaneran (6-nitroimidazol-6-thioguanine) was added to 1 mL plasma as the internal standard and CdA was extracted using ethyl acetate. A Perkin-Elmer C18, 3 mu, 8 cm column was used for the separation of CdA and the internal standard from endogenous compounds in the sample with a mixture of sodium phosphate buffer 10 mM, methanol and acetonitrile (85:10:5, pH = 3.0) as the mobile phase. The sensitivity of the method (1 nM) allows the determination of CdA in plasma 24 h after the administration of 0.14 mg/kg as a 2 h infusion.
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PMID:Determination of 2-chloro-2'-deoxyadenosine in human plasma. 168 27

Hairy-cell leukemia is an unusual chronic lymphoid leukemia with distinctive clinical and pathological features. The management of this disorder has been revolutionized in the last decade with the discovery of the efficacy of alpha interferon and the inhibitors of adenosine metabolism, deoxycoformycin and chlorodeoxyadenosine. The best treatment protocol for hairy-cell leukemia has not yet been defined. Patients may still die from their disease, particularly in the early phases of treatment. Conversely, some patients appear not to require treatment and others respond well to splenectomy and need no further therapy. An individualized clinical approach is recommended, with a role for splenectomy in the patient with cytopenia and a relatively low number of hairy cells in the bone marrow. The first line drug treatment remains interferon alpha given for 12-18 months, following which the patient is observed for clinical relapse. Deoxycoformycin remains a useful experimental agent but cannot be recommended for routine clinical use until issues of long term toxicity are resolved. Chlorodeoxyadenosine is a very promising experimental drug, but confirmation of the early data in larger group trials is required. Similarly the adjunctive use of granulocyte colony stimulating factor appears useful, but will need further study in larger groups of patients. There is little or no role for alkylating agents or more intensive chemotherapy in the modern management of hairy-cell leukemia.
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PMID:Treatment of hairy-cell leukemia. 170 7

2-Chlorodeoxyadenosine is a simple purine nucleoside that has previously been shown to be effective in the treatment of low-grade malignant disorders of lymphoid tissue, including chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Because of these encouraging results, we treated 12 patients with another low-grade B-cell neoplasm, hairy-cell leukemia. The patients received 2-chlorodeoxyadenosine (0.1 mg per kilogram of body weight per day) by continuous infusion for seven days. All the patients responded to treatment. Eleven had complete remissions characterized by the normalization of peripheral blood and bone marrow and disappearance of tumor masses. The longest remission has been 3.8 years. None of the patients have relapsed, and the median duration of remission has been 15.5 months. No serious toxic reactions occurred as a result of 2-chlorodeoxyadenosine therapy. These results suggest that 2-chlorodeoxyadenosine may be the most effective therapy available for hairy-cell leukemia. The administration of 2-chlorodeoxyadenosine resulted in a higher rate of complete remission than is observed with interferon alfa, and it required no maintenance therapy. Its toxicity may be lower than that of deoxycoformycin, and the responses were achieved with single courses of treatment.
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PMID:Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. 196 13

The design and synthesis of (E)- and (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (6 and 13, respectively), a new class of mechanism-based inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, is described. A number of analogues of 6 and 13 were synthesized in order to determine the structure-activity relationship necessary for inhibition of the enzyme. Substitution of chlorine for fluorine in 6 (i.e. 44), addition of an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent electrophile derived from oxidation of the 3'-hydroxyl of 6 or 13 to the ketone (i.e. 3 and/or the E-isomer). Consistent with the proposed mechanism of inactivation of SAH hydrolase by 6, 13, and 14 was the observation that incubation of purified rat liver SAH hydrolase with 6 resulted in release of 1 equiv of fluoride ion (by 19F NMR) and incubation with 14 resulted in release of 2 equiv of fluoride ion. The general synthetic route developed for the synthesis of the title nucleosides utilized the fluoro Pummerer reaction for the introduction of fluorine into the requisite precursors. Preliminary antiretroviral data from Moloney leukemia virus (MoLV) is presented and correlates with SAH hydrolase inhibition. Antiviral activity (IC50 against MoLV) ranged from 0.05 to 10 micrograms/mL.
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PMID:4',5'-unsaturated 5'-halogenated nucleosides. Mechanism-based and competitive inhibitors of S-adenosyl-L-homocysteine hydrolase. 199 89


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