Cerebrospinal fluid purine metabolites after complex febrile convulsions

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and uric acid were determined in cerebrospinal fluid (CSF) of 15 children after complex febrile seizures (CFS) and in 27 after simple febrile seizures (SFS), and compared with those in a control group of 63 children. There was no statistically significant difference between the groups for any of these metabolites, suggesting that CFS and SFS neither significantly disturb the metabolism of nucleotides, nucleosides or bases nor significantly deplete neuron adenosine triphosphate levels.     

兔急性脑缺氧时脑及脑脊液内腺嘌呤核苷含量的变化

本文报告了由低张性低氧血症所致兔急笥脑缺氧时脑组织内腺苷、次黄嘌呤核苷及次黄嘌呤水平分别从正常对照的５３．３±２．９、１１５．６±１１．８及１８６．５±１０．３增至８１６．４±５９．０、１０４９．７±３７．５及７０４．４±５５．３μＭ／ｇ（Ｘ±ＳＤ），各组间Ｐ值均＜０．０１至０．０５。同步测定的脑脊液中三种腺嘌呤核苷水平分别从正常对照的１．６±０．８、５．１±１．０及１３３．９±５０．８增至７．０     

Inosine 5′-phosphate dehydrogenase activity in normal and leukemic blood cells

Summary The enzyme inosinic acid dehydrogenase (EC 1.2.1. [14]) was measured and partially purified (10- to 15-fold) from normal and leukemic leukocytes. From the normal blood cells, the highest activities could be detected in lymphocytes and bone marrow cells. Dependent on the blast cell count, the leukemic IMP dehydrogenase had a higher mean specific activity than the enzymes of fractionated, immature bone marrow cells, or normal granulocytes. The partially purified enzymes from the various blood cells were apparently identical; they exhibited hyperbolic substrate saturation kinetics and were inhibited by a number of purine nucleotides. For the leukemic blast cell enzyme, theK _m values for the substrates, IMP and NAD⁺, were 28±11; 227±98 µM, and 34±10; 240±67 µM for the partially purified enzyme from normal, immature bone marrow cells.The hypoxanthine-guanine and adenine phosphoribosyltransferase activities increased in the leukemic cells when compared with mature granulocytes, but nearly always showed similar activities when compared with the fractionated bone marrow cells. Only one of the 30 investigated leukemic patients exhibited a marked decrease in hypoxanthine phosphoribosyltransferase activity of 0.5 nmol/mg/h. The phosphoribosyltransferase-specific activities of the leukemic cells are more variable than for the normal ones and no correlation of enzyme activities and blast cell count was apparent.

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Abbreviations A-PRT adenine phosphoribosyltransferase - HG-PRT hypoxanthine-guanine phosphoribosyltransferase - PRPP 5-phosphoribosyl-1-pyrophosphate - ALL acute lymphocytic leukemia - AML acute myelogenous leukemia - CLL chronic lymphatic leukemia - CML chronic myelogenous leukemia - AMMOL acute myelomonocytic leukemia This study was supported by the Deutsche forschungsgemeinschaft Be 458/4     

Molecular and functional characterization of the first nucleobase transporter gene from African trypanosomes

African trypanosomes are unable to synthesize purines and depend upon purine nucleoside and nucleobase transporters to salvage these compounds from their hosts. To understand the crucial role of purine salvage in the survival of these parasites, a central objective is to identify and characterize all of the purine permeases that mediate uptake of these essential nutrients. We have cloned and functionally expressed in a purine nucleobase transport deficient strain of Saccharomyces cerevisiae a novel nucleobase transporter gene, TbNT8.1, from Trypanosoma brucei. The permease encoded by this gene mediates the uptake of hypoxanthine, adenine, guanine, and xanthine with Kms in the low micromolar range. The TbNT8.1 protein is a member of the equilibrative nucleoside transporter (ENT) family of permeases that occur in organisms as diverse as protozoa and mammals. TbNT8.1 is distinct from other ENT permeases that have been identified in trypanosomes in utilizing multiple purine nucleobases, rather than purine nucleosides, as substrates and is hence the first bona fide nucleobase permease identified in these parasites. Furthermore, unlike the mRNAs for other purine transporters, TbNT8.1 mRNA is significantly more abundant in insect stage procyclic forms than in mammalian stage bloodstream forms, and the TbNT8.1 permease thus may represent a major route for purine nucleobase uptake in procyclic trypanosomes.     

Białaczka włochatokomórkowa oporna na standardową terapię analogiem puryn – opis przypadku i przegląd piśmiennictwa

Hairy cell leukemia (HCL) is a rare, chronic lymphoproliferative disorder. Currently, purine nucleoside analogs (PNA) constitute the first line treatment of HCL. Cladribine could induce long lasting remission in majority of patients with only a single cycle of therapy. In fact the relapsed patients could be treated successfully with cladribine too. Sometimes we observe the resistance to PNA. Rituximab and chemoimmunotherapy (rituximab plus cladribine) are effective in treatment of refractory HCL.We present a case of a 64-year-old man who was treated with rituximab after second progression of HCL. In March 2011, rituximab was given at a dose of 375 mg/m² i.v. once a week for eight weeks, with result of achievement of PR. During the last hospitalization in March 2013 the persistence of PR was confirmed.     

Enzymes of the purine interconversion system in chronic lymphatic leukemia: Decreased purine nucleoside phosphorylase and adenosine deaminase activity

Summary Activities of adenosine deaminase (ADA), adenosine kinase (AK), adenine phosphoribosyltransferase (APRT), hypoxanthine guanine phosphoribosyltransferase (HGPRT), and purine nucleoside phosphorylase (PNP), all enzymes of the purine interconversion system, were determined in lymphocytes of 25 patients with chronic lymphatic leukemia (CLL) and in 23 controls. A statistically significant decrease of PNP activities and a reduction of ADA activities at borderline levels were found in the patients, whereas for the other enzymes assayed no deviation from normal values was observed.This work was supported in part by the Austrian Research Fund (Project No. 3796).     

The place of cladribine in the treatment of chronic lymphocytic leukemia: a 10-year experience in Poland

Cladribine (2-CdA) is structurally similar to another purine analog, fludarabine (FA), recently accepted in several centers as the first-line treatment in chronic lymphocytic leukemia (CLL). Unfortunately, there is less experience with the use of 2-CdA than with FA in patients with CLL in the majority of Western countries. In the last decade we performed several phase II studies and two phase III randomized trials to evaluate the activity and toxicity of 2-CdA in previously treated and untreated patients with CLL. We have also compared the results of Polish studies with the data presented by other investigators. Similarly to FA this agent has been found to be more effective in previously untreated CLL than in patients refractory to or relapsed after conventional therapy with alkylating agents. In different studies the overall response (OR) rate ranged from 70 to 85% and complete response (CR) from 10 to 47%. Higher CR and OR rates in CLL patients treated with 2-CdA and prednisone than with chlorambucil and prednisone were confirmed in our multicenter, randomized study. Subsequently, we performed a multicenter, randomized study comparing 2-CdA alone with a combination of 2-CdA and cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC). Our updated results seem to indicate that the CC program used as a first-line therapy in CLL gives higher CR and OR and better elimination of minimal residual disease (MRD) than 2-CdA alone. CC is also less myelotoxic than CMC. More recently, we have undertaken a phase II study to determine the efficacy and toxicity of 2-CdA combined with the anti-CD20 monoclonal antibody rituximab in CLL and other refractory or relapsed indolent lymphoproliferative disorders. The preliminary results seem to be better than in similar patients previously treated in our institution with 2-CdA alone. In conclusion, the studies performed in the last decade in Poland and other countries have shown that 2-CdA used alone or in combination with other agents is, similarly to FA, a highly active and relatively safe agent in previously treated and untreated patients with CLL.     

Purine metabolism in human lymphocytes

Summary In peripheral human blood lymphocytes the uptake and metabolism of adenine, guanine, and hypoxanthine was investigated. This was achieved by incubation of purified lymphocytes with¹⁴C-purine bases, separation of cells from the incubation medium by a rapid filtration technique, and subsequent separation of the acid soluble material by thin-layer chromatography. No preferential uptake for one of the purine bases was observed. In all cases only traces of¹⁴C-purine bases not added originally and labeled nucleosides could be demonstrated. Approximately 2/3 of adenine and 1/2 of guanine or hypoxanthine were converted to nucleotides. Separation of formed nucleotides showed that adenine and guanine were metabolized mainly to their corresponding nucleotides; hypoxanthine was converted to a considerable amount to adenine nucleotides and only to a small proportion into its own nucleotides. These results demonstrate the predominance of adenine nucleotide formation in normal human lymphocytes.The study was supported by a grant of Fonds zur Förderung der wissenschaftlichen Forschung Österreichs (project No. 3038)