Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two of the new anticancer drugs recently synthesized in our laboratory from conjugation of ara-C2 and several corticosteroids linked through a phosphodiester bond include prednisolone- (I) and prednisone-p-ara-C (II). They were demonstrated to be enzymatically hydrolyzed to the corresponding steroid and ara-CMP and the latter was further shown to be hydrolyzed to ara-C by phosphodiesterase I, snake venom, 5'-nucleotidase, and acid phosphatase. However, the conjugates were shown to be resistant to hydrolysis by alkaline phosphatase. The activity of conjugates I and II against L1210 lymphoid leukemia in female mice (C3D2F1/J) was significantly greater than that of ara-C alone or in combination with the steroid. In fact, when the optimum dosage of 75 (mumol/kg)/day x 5 was used, the administration of ara-C alone was followed by an increased life span (ILS) of 45%. This result is similar to that previously reported. With the same equimolar doses of mixtures of ara-C and either prednisolone or prednisone, the ILS values were 40 and 44%, respectively. However, when the conjugates were used, the ILS values were 89 and 100% respectively. These findings seem promising and have provided the bases for continued study of these new compounds.
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PMID:Nucleoside conjugates as potential antitumor agents. 2. Synthesis and biological activity of 1-(beta-D-arabinofuranosyl)cytosine conjugates of prednisolone and prednisone. 11 58

Three patients with amyloidosis in whom hepatomegaly was the main sign ara presented. In all cases jaundice coexisted which is regarded as a rare sign in amyloidosis. Attention is called to the diagnostic difficulties of amyloidosis especially without a preceding clinically overt disease process. The presence of a particularly high activity of alkaline phosphatase in the serum, and focal absence of 99Tc uptake by the hepatic macrophage system in liver scintigram suggested liver tumour. However, demonstration of monoclonal protein in blood, urine or ascitic fluid, or raised level of alpha 2 globulin, should call attention to the possibility of liver amyloidosis. The authors stress the usefulness of the method of preincubation of tissue biopsy specimens in potassium hypermanganate during routine staining with Congo red for differentiation of amyloid AA from amyloid AL.
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PMID:[Diagnostic difficulties in hepatic amyloidosis--clinical analysis and autopsy data of 3 cases]. 226 76

Activity of cobalt activated acylase, gamma-glutamyltransferase, leucylaminopeptidase and alanylaminopeptidase in serum and liver of mice with transplantable leukemias (L1210, L1210/ara-C, L1210/CH3-G, AKSL-4, plasmacytoma ADJ-PC-5) were determined. Adenosinotriphosphatase, 5'-nucleotidase and alkaline phosphatase were histochemically localized in lymphatic nodes and spleen. Among the investigated enzymes the rise in serum activity of cobalt activated acylase and gamma-glutamyltransferase was demonstrated. A substantial increase of leucylaminopeptidase and alanylaminopeptidase was shown in the liver. A decrease in the histochemical reactions of all the studied enzymes was observed.
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PMID:Enzyme activity in mice with transplantable leukemia. 287 46

The potentiation of radiation damage, which can be accomplished by the inhibition of repair, is estimated from published studies of repair deficient mutants. Sensitization factors as high as 10 have been achieved. Because it has previously been suggested that the most probable lethal lesion is a DNA double strand break (DSB), it is not surprising that cells deficient in repairing this type of damage are the most radiosensitive. The structures of DNA DSBs and other Locally Multiply Damaged Sites (LMDS) (involving both single strand breaks (SSB) and base damage sites) are reviewed, together with the processes by which cells may attempt to repair these lesions. Repair processes occur in competition with damage fixation, again, mechanisms of damage fixation are predicted from studies in model systems. A strategy for inhibiting the repair processes is devised that consists of holding the first SSB constituent of the LMDS open by repairing in the presence of deoxynucleoside analogues, such as ara-C, so that there is a higher probability of the formation of a DSB upon cleavage of the second site (on the other strand) by hydrolysis of a labile bond or by endonuclease cleavage of a base damaged site. To achieve preferential sensitization of tumor vs. normal tissue it may be possible to take advantage of the deficiency in alkaline phosphatase in tumor vs. normal vasculature, that is, in analogy with treatment with WR-2721. The deoxynucleoside analogue would be delivered together with the phosphate ester (deoxynucleotide) of the correct deoxynucleoside, for example, ara-C, in the presence of deoxycytidine monophosphate (dCMP). Higher alkaline phosphatase levels in normal tissue capillaries would hydrolyse the dCMP to deoxycytidine, which competes effectively with ara-C in repair replication.
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PMID:Mechanisms of DNA repair and their potential modification for radiotherapy. 352 85

In vitro studies of certain lymphoid tumor cells show potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C) effects by uridine because it elevates intracellular uridine triphosphate, resulting in increased ara-C triphosphate levels. Seven-day continuous i.v. infusions of uridine at 123 mg/kg/h (2.5 g/sq m/h) were studied in 5 male beagles. Steady state levels of uridine were reached within 4 to 6 h and ranged from 2 to 5 X 10(-4) M over the course of the infusion. Steady state uracil levels ranged from 4 to 10 X 10(-4) M. After the end of infusion, uridine and uracil levels fell with a half-life of approximately 15 and 18 min, respectively. Toxicity in 2 dogs treated at this dose was limited to minimal diarrhea and a transient rise of alkaline phosphatase to 2 to 3 times normal. No drug toxicity was evident at sacrifice on Days 7 or 72. Three dogs received a 7-day infusion of ara-C plus uridine followed approximately 4 weeks later by an infusion of ara-C alone (or the same drugs in the reverse sequence). Coinfusion of 2.5 or 5.0 mg/kg/day (50 or 100 mg/sq m/day) of ara-C had no significant effects on uridine plasma levels or postinfusion half-lives. Similarly, no consistent effect was seen of uridine on ara-C plasma levels. Uridine coinfusion with ara-C resulted in a definite potentiation of myelosuppression; at 5.0 mg/kg/day X 7 of ara-C white blood cell and platelet nadirs (X 10(3)/microliters) were 0.8 and 15 as compared to 3.6 and 66, respectively, with ara-C alone. One-third of the dogs developed reversibly elevated transaminases with the combination treatment. The results show that a minimally toxic dose of uridine enhances bone marrow and probably hepatic toxicity of coadministered ara-C.
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PMID:Pharmacology and toxicology of a seven-day infusion of 1-beta-D-arabinofuranosylcytosine plus uridine in dogs. 398 95

Four types of 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates with poly-L-glutamic acid (PLGA) or poly-N5-(2-hydroxyethyl)-L-glutamine (PHEG) were prepared in an attempt to enhance the efficacy of the drug in simple dosage schedules. The conjugates were made by linking ara-C to the carboxyl groups of PLGA directly at N-4 of ara-C (ara-C:PLGA) or indirectly through the 2-aminoethylphosphoryl or 6-aminohexylphosphoryl side chain which had been introduced to C-5' of ara-C, 1-[5'-(2-aminoethylphosphoryl)-beta-D-arabinofuranosyl]cytosine: PLGA [araCMP(C2):PLGA and 1-[5'-(6-aminohexylphosphoryl)-beta-D-arabinofuranosyl]cytosine:++ +PLGA, respectively, or made by converting the remaining carboxyl groups in the PLGA conjugates to the 2-hydroxyethylamide groups [ara-C:PHEG, ara-CMP(C2):PHEG, 1-[5'-(6-aminohexylphosphoryl)-beta-D-arabinofuranosyl]cytosine:++ +PHEG]. Studies in vitro showed that the conjugates had decreased cytotoxicity against L1210 cells when compared with that of ara-C. Studies in vivo showed that all of the conjugates, except ara-CMP(C2):PLGA, had a greater antitumor activity than did ara-C in L1210 tumor-bearing BALB/c X DBA/2 F, (hereafter called CD2F1) mice (inoculum, 1 X 10(5) cells i.p. on Day 0) which were treated by a single i.p. injection of either the conjugates or the control ara-C on Day 1. The largest antitumor activity [increased life span (ILS) 170%] was observed with a dosage of 50 mg (equivalent ara-C per kg) of ara-C:PHEG. When CD2F1 mice which had been inoculated i.p. with 1 X 10(5) L1210 cells were treated with an i.p. injection of 12.5 or 25 mg (equivalent ara-C per kg) of ara-C:PHEG daily for 5 days starting from Day 1, 2 of 5 mice survived more than 42 days, and the ILS of the remaining mice was 153 and 184%. The injections of 3.2 mg (equivalent ara-C per kg) of ara-C:PHEG showed a moderate antitumor activity with an ILS of 113% which was similar to the ILS (119%) found when unconjugated ara-C (400 mg/kg) was used to treat tumor-bearing mice. In in vitro release experiments, ara-C was released slowly from ara-C:PLGA at pH 7.4, and ara-CMP(C2):PLGA was chemically stable but cleaved by phosphodiesterase, acid phosphatase, and alkaline phosphatase to give mainly 1-beta-D-arabinofuranosylcytosine 5'-monophosphate.
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PMID:Antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugated with polyglutamic acid and its derivative. 619 62

Diamine oxidase (DAO; EC 1.4.3.6) is an enzyme found in high activity in the mature upper villus cells of rat intestinal mucosa and only in very low activity in all other tissues except for the placenta in the pregnant rat. The present study was designed to investigate whether plasma and mucosal DAO could be used to monitor the timing and severity of injury and recovery of the intestinal mucosa after administration of the chemotherapeutic agent 1-beta-D-arabinofuranosylcytosine (ara-C). A dose of 0.3 g/kg s.c. every 8 hr for 6 doses was given to adult Lewis x Brown Norway rats. This resulted in death of the proliferating crypt cells, followed by regeneration of the mucosa from the surviving crypt cells, with recovery by Day 8. This mucosal damage and recovery was reflected by histological changes and a decrease in activity of mucosal disaccharidases and alkaline phosphatase. Both mucosal and plasma DAO levels also fell markedly to less than 10% of basal levels (N = 30, p less than 0.005) by Day 4 and recovered with a time course similar to the histological and biochemical changes indicative of injury and recovery. With increasing dosage and/or increasing duration of ara-C treatment, mucosal injury was progressive, with increasing loss of both plasma and mucosal DAO levels as compared to controls (N = 38, p less than 0.005). Plasma DAO levels in three patients with leukemia following ara-C chemotherapy decreased markedly to less than 30% of basal pretreatment levels (p less than 0.05) by Days 9 to 12, with a time course that was compatible with clinical intestinal mucosal injury. Our data document that plasma DAO levels reflect the mucosal injury and subsequent recovery after ara-C treatment in the rat and humans. Thus, plasma DAO may serve as a marker of the integrity of the intestinal mucosa after chemotherapy.
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PMID:Diamine oxidase as a plasma marker of rat intestinal mucosal injury and regeneration after administration of 1-beta-D-arabinofuranosylcytosine. 678 36

Six 5'-(steroid-21-phosphoryl)-1-(beta-D-arabinofuranosyl)cytosines have been prepared and evaluated against L1210 lymphoid leukemia in culture and in mice (C3D2F1/J). These include the ara-C conjugates of 11-deoxycorticosterone (5a), corticosterone (5b), cortexolone (5c), fludrocortisone (5d), 6 alpha-methylprednisolone (5e), and dexamethasone (5f). When the optimum dosage of ara-C [38 (mumol/kg)/day X 5] was given to mice bearing L1210, the ILS value found was 89%. A simple mixture of each steroid and ara-C gave ILS values that were on the whole significantly less than that of the parent nucleoside. However, of six conjugates, all but two (5d and 5f) were more active than ara-C at their optimal doses. Both corticosterone- (5b) and cortexolone-p-ara-C (5c) were especially effective at the respective optimal doses of 76.7 and 115 (mumol/kg)/day X 5. These gave ILS values of 200% each. All of the conjugates were demonstrated to be enzymatically hydrolyzed to the corresponding steroid and ara-CMP, and the latter was further shown to be hydrolyzed to ara-C by phosphodiesterase I, 5'-nucleotidase, and acid phosphatase. However, they were shown to be resistant to hydrolysis by alkaline phosphatase.
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PMID:Nucleoside conjugates as potential antitumor agents. 3. Synthesis and antitumor activity of 1-(beta-D-arabinofuranosyl)cytosine conjugates of corticosteroids. 745 87

The mode of action of the differentiation inducer 1-beta-D-arabinofuranosylcytosine (ara-C) is as yet unknown. We have analyzed the role of c-myc expression in ara-C-induced differentiation of K562 human erythroleukemia cells. Six hours after differentiation induction, c-myc expression is down-regulated transiently. This was followed by the onset of cell differentiation together with a final c-myc 'down-regulation' at 24 h after treatment. This regulation of expression may be caused by hypermethylation of c-myc DNA sequences, which we find to follow a similar pattern. We propose that the loss of c-myc expression might be a necessary prerequisite for ara-C-induced differentiation. This hypothesis was tested by transfecting a constitutive c-myc expression construct into K562 cells prior to ara-C treatment. By following the differentiation parameters cell morphology, benzidine staining (hemoglobin monitored), and alkaline phosphatase activity (presence of mature red blood cell antigen monitored) in cells expressing cotransfected LacZ marker gene, it was demonstrated that the introduction of the c-myc expression plasmid blocked ara-C-induced differentiation. We conclude that loss of c-myc expression mediated the differentiation found in ara-C-treated K562 cells.
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PMID:Essential role of c-myc in ara-C-induced differentiation of human erythroleukemia cells. 805 66

A new sensitive method for the measurement of 1-beta-D-arabinofuranosyl-CTP (ara-CTP), an intracellular active metabolite of 1-beta-D-arabinofuranosylcytosine (ara-C), in human materials in vivo has been established. An acid-soluble fraction containing ara-CTP was extracted from blastic cells by ara-C treatment with trichloroacetic acid (final concentration, 0.3 M) neutralized with an equal volume of cold freon containing 0.5 M tri-n-octylamine. The ara-CTP fraction was separated from the acid -soluble fraction by high-performance liquid chromatography (TSK gel diethylaminoethyl-2 SW column) eluted with 0.05 M phosphate buffer (pH 6.9) and 20% acetonitrile. ara-CTP was lyophilized, dephosphorylated to ara-C by incubation with 10 units alkaline phosphatase for 12 h at 55 degrees C, and measured by RIA using anti-ara-C serum. Recovery through the whole procedure was 92%. In the human chronic myelogenous leukemia cell line K562, the intracellular ara-CTP levels produced when the cells were incubated with ara-c were assayed as above, and they showed a linear increase depending on Ara-C concentrations from 0.01 to 10 microns, demonstrating a very close correlation with the labeled ara CTP levels yielded by cells on incubation with radiolabeled ara-C (r2 = 0.99). The detection limit was 0.1 pmol/5 x 10(6) cells, and a sample amount of only 5 x 10(6) cells was enough for each assay. In the clinical applications, our method proved capable of detecting a wide concentration range of ara-CTP produced when patients were treated with ara-C or its derivatives from very low to intermediate doses. No radiolabeled drug was necessary. The method was very useful for in vivo pharmacodynamic studies of ara-C therapy.
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PMID:A new sensitive method for determination of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate content in human materials in vivo. 862 Apr 96


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