Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxyadenosine (AdR) appears to be central to the molecular events mediating immunodeficiency in children born with adenosine deaminase (ADA) deficiency but it is still uncertain whether lymphotoxicity is due to AdR directly inhibiting transmethylation reactions in which S-adenosylmethionine is the methyl group donor, or is due to phosphorylation of AdR to deoxyadenosine triphosphate (dATP) which then inhibits ribonucleotide reductase or is due to other mechanisms. Using AdR and the ADA inhibitor deoxycoformycin (dCF) and assessing cell viability, nucleoside incorporation into RNA and DNA, as well as measuring deoxyribonucleoside triphosphate (dNTP) concentrations and S-adenosylhomocysteine (SAH) hydrolase activity, we have studied various types of human lymphoid cells and demonstrated in them the relative importance of the above two mechanisms of AdR toxicity. Treatment of normal resting peripheral blood lymphocytes in culture with AdR and dCF resulted in impaired viability. Although elevated dATP levels as well as decreased SAH hydrolase activities were both observed, the failure of a known inhibitor of ribonucleotide reductase (hydroxyurea) to produce toxicity, and the inability of deoxycytidine (CdR) to achieve a rescue effect, point to another mechanism, possibly inhibition of trans-methylation or ATP depletion being the more likely causes of toxicity in resting lymphocytes. The same mechanism may well account for the rapid and severe lymphopenia in patients treated with dCF. On the other hand, in cultured lymphoblasts in the exponential phase of growth. AdR and dCF produced marked inhibition of growth and cell death both in a Thy-ALL line and in a c-ALL line, in the absence of significant inhibition of SAH hydrolase, but with a substantial elevation in dATP concentrations and depressed levels of the other dNTP. Minor toxicity occurred in a proliferating B lymphoblast line despite almost complete inactivation of SAH hydrolase. These observations indicate inhibition of ribonucleotide reductase as the more likely mechanism of toxicity in rapidly proliferating lymphocytes. Other T-cells actively synthesizing DNA, such as PHA-stimulated or MLC activated lymphocytes and T-lymphoid colony forming cells, are also likely to be affected by the same mechanism. Indeed in PHA-stimulated lymphocytes, deoxycytidine caused significant although incomplete rescue from toxicity due to dCF and AdR. In patients with ADA deficiency or treated with ADA inhibitors, both mechanisms could be operative. These observations are also relevant to the possible use of dCF and AdR as immunosuppressive agents and for the removal of T-cells or residual Thy-ALL blasts from bone marr
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PMID:Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: relevance to the therapeutic use of inhibitors of adenosine deaminase. 623 Oct 47

Accumulation of dATP derived from 2'-deoxyadenosine (dAdo), causing inhibition of ribonucleotide reductase and depletion of the other deoxynucleotide substrates required for DNA synthesis, has been suggested as the cause of the lymphopenia and immune defect in inheritable deficiency of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4). dAdo also inactivates the enzyme S-adenosylhomocysteine hydrolase (AdoHcyase; S-adenosyl-L-homocystein hydrolase EC 3.3.1.1) which is involved in the catabolism of S-adenosyl-L-homocysteine (AdoHcy), both a product and a potent inhibitor of S-adenosylmethionine-dependent transmethylation. We have tried to determine whether inactivation of AdoHcyase might also contribute to dAdo toxicity to adenosine deaminase-inhibited cells. dAdo rapidly inactivates intracellular AdoHcyase and causes the accumulation of AdoHcy in WI-L2 human B lymphoblastoid cells. Low concentrations of adenosine (Ado), which block binding of dAdo to purified AdoHcyase, prevented inactivation of intracellular AdoHcyase and also lessened the growth-inhibitory effect of dAdo. A mutant of this cell line which lacks Ado kinase and accumulated endogenously synthesized Ado was resistant to the effects of dAdo on both growth and AdoHcyase activity. The mutant also accumulated far less dATP from dAdo than did its parent and was resistant to the inhibitory effect of dAdo on DNA synthesis, indicating the Ado kinase is involved in dAdo phosphorylation in these cells. Combinations of deoxycytidine, thymidine, and deoxyguanosine that could prevent dATP-mediated depletion of deoxynucleotide pools but not AdoHcyase inactivation were less effective than Ado in preventing dAdo toxicity to normal lymphoblasts. Our results suggest that inactivation of AdoHcyase, as well as dATP accumulation, contributes to dAdo toxicity.
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PMID:Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation. 625 19

Purine nucleoside analogues are a new class of drugs with activity against non-dividing lymphocytes. They should thus play a major role in the treatment of low grade lymphoid malignancies. These drugs have been shown to have strong effect in DNA synthesis on actively dividing cells, mainly through interference with DNA polymerases and ribonucleotide reductase. However, the cell cycle kinetics of low grade lymphocytic lymphomas is characterized by the presence of very low growth fractions. Hence, the action of these drugs in slowly progressing lymphoid malignancies cannot be accounted by the same mechanism observed in actively proliferating tumors and needs to be explained through activity against quiescent resting lymphocytes. Recent work has stressed the role of purine analogues in inducing programmed cell death of quiescent lymphocytes, which could be explained through the induction of accelerated DNA strand breaks. This process leads to consumption of NAD for poly(ADP-ribose) synthesis, which could induce critical depletion of ATP. As this action extends to normal resting lymphocytes deleterious effects related to their immunosuppressive action are also observed, i.e. prolonged lymphopenia predominating in T cells and especially in CD4 subset, increased frequency of opportunistic infections and perhaps increase in autoimmune complications like autoimmune hemolytic anemia. Nevertheless, beneficial effects of this immunosuppressive action have also been reported in the prevention of graft-versus-host disease, graft rejection and in some autoimmune diseases like multiple sclerosis. Work needs to be carried out to define better the mechanisms of action of these drugs on the different immunological effectors, as well as studies in animal models of transplantation and autoimmune diseases.
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PMID:Adverse and beneficial immunological effects of purine nucleoside analogues. 913 60

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine, Vion Pharmaceuticals, New Haven, CT) is an inhibitor of the M2 subunit of ribonucleotide reductase (RR). Preclinical testing demonstrates synergy between 3-AP and gemcitabine. Phase I studies of the combination have suggested tolerability and some initial evidence of efficacy. Therefore, a phase II study of gemcitabine plus 3-AP in advanced pancreatic carcinoma was undertaken. In this two-step phase II trial, patients with advanced pancreatic adenocarcinoma who had not received prior chemotherapy for advanced disease were treated with 3-AP 105 mg/m(2) given over 2 h. Four hours after the 3-AP infusion was completed, gemcitabine 1,000 mg/m(2) was given over 30 min. Both drugs were given on days 1, 8 and 15 of a 28-day cycle.Twenty-six patients were enrolled to the study. One patient withdrew consent prior to receiving any treatment and is excluded from all further analyses. Four patients discontinued treatment due to adverse effects. Grade 3/4 hematological adverse events included neutropenia, thrombocytopenia, lymphopenia, leukopenia and anemia and the most frequent non-hematological adverse events were fatigue and pain. No objective responses were observed. Eleven patients had stable disease (SD). In five of these eleven patients, SD lasted for more than 6 months. The median time to progression was 4.1 months and the 6 month progression-free survival rate was 29%. The median survival was 9.0 months with a 1-year survival of 28.0%. The combination of 3-AP and gemcitabine is associated with moderate toxicity in patients with advanced pancreatic cancer. This two-stage trial was stopped after stage I due to lack of antitumour activity. On the basis of this clinical trial, the combination of gemcitabine and 3-AP at this dose and schedule does not warrant further study in this patient population.
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PMID:A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret hospital Phase II consortium. 1758 72