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

---

Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4)-deficient patients recently were found to have abnormally high levels of dATP, a negative allosteric effector of ribonucleotide reductase (ribonucleoside-diphosphate reductase, 2'-deoxyribonucleoside-diphosphate:oxidized thioredoxin 2'-oxidoreductase, EC 1.17.4.1). Therefore it was proposed that the immunodeficiency associated with adenosine deaminase deficiency is mediated through inhibition of ribonucleotide reductase and hence DNA replication. HeLa cells, treated with an adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine, and deoxyadenosine to mimic the adenosine deaminase-deficient state, were monitored to determine directly the effects on ribonucleotide reductase activity and levels. A low concentration of erythro-9-(2-hydroxy-3-nonyl)adenine, which did not inhibit cell growth, nevertheless retarded the cells in G2 + M phase of the cell cycle and increased reductase activity. Reductase activity was also elevated in cells treated with a low level of deoxyadenosine which did not affect the cell cycle or cell growth. However, ribonucleotide reductase activity was reduced to one-half of the control value in cells treated with either enough deoxyadenosine to inhibit cell growth or with a combination of erythro-9(2-hydroxy-3-nonyl)adenine and deoxyadenosine, each at concentrations which individually do not inhibit cell growth. Removal of deoxynucleotides, particularly dATP, from these extracts increased ribonucleotide reductase activity to several-fold higher than control values. The reduced activity of ribonucleotide reductase in the simulated adenosine deaminase-deficient HeLa cells provides direct evidence for the thesis that adenosine deaminase deficiency disease is mediated through elevated levels of dATP which inhibit ribonucleotide reductase. In addition, the cell cycle patterns and ribonucleotide reductase levels suggest that the regulatory substance(s) that controls the level of ribonucleotide reductase is not operative until the late S or G2 phase of the cell cycle.
...
PMID:Adenosine deaminase impairment and ribonucleotide reductase activity and levels in HeLa cells. 699 99

We and other groups have recently reported the potentiation by ribonucleotide reductase inhibitors such as hydroxyurea of the anti-human immunodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2',3'-dideoxynucleosides in both resting and phytohemagglutinin-stimulated peripheral blood mononuclear cells. Little agreement prevails, however, as to the mechanism of the synergistic effects described. We report here that in phytohemagglutinin-stimulated peripheral blood mononuclear cells, two mechanisms exist for the potentiation of the anti-HIV-1 activity by low-dose hydroxyurea of the purine-based dideoxynucleoside 2',3'-dideoxyinosine and the pyrimidine-based dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine. For 2',3'-dideoxyinosine, the enhancement arises from a specific depletion of dATP by hydroxyurea, resulting in a favorable shift of the 2',3'-dideoxyadenosine 5'-triphosphate/dATP ratio. For the pyrimidine dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine, the more modest anti-HIV enhancement results from hydroxyurea-induced increases of pyrimidine kinase activities in the salvage pathway and, hence, increased 5'-phosphorylation of these drugs, while depletion of the corresponding deoxynucleoside 5'-triphosphates (dTTP and dCTP) plays no significant role.
...
PMID:Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2',3'-dideoxynucleoside activities against replication of human immunodeficiency virus. 766 90

The effects of hydroxyurea (HU), an inhibitor of ribonucleotide reductase, on the replication of human immunodeficiency virus type 1 (HIV-1) in activated peripheral blood mononuclear cells were studied. The inhibition of HIV-1 replication by HU alone was dose dependent, with a 90% inhibitory concentration of 0.4 mM, a plasma concentration tolerated by patients with oncological diseases. HU at lower concentrations (< 0.1 mM) was found to potentiate the antiviral activity of 2',3'-dideoxyinosine (ddl), 3'-azido-2',3'- dideoxythymidine, and 2',3'-dideoxycytidine against HIV-1, with the potentiation being ddl greater than 3'-azido-2',3'- dideoxythymidine = 2',3'-dideoxycytidine. In the presence of 0.1 mM HU, the 90% inhibitory concentration of ddl was reduced by 6-fold in activated peripheral blood mononuclear cells. The potentiating effect of HU on ddl action was time dependent, with the greatest inhibition of HIV-1 growth being seen when HU was present during and after virus adsorption, i.e., apparently coinciding with the time of proviral DNA synthesis. A brief incubation of activated cells with HU and ddl at low concentrations before virus exposure reduced p24 production by > 50%. Analyses using high performance liquid chromatography and enzymatic assays suggested that the greater degree of potentiation by HU of the action of ddl, compared with the other dideoxynucleosides, is due to the more effective inhibition by HU of dATP synthesis, compared with the synthesis of the other deoxynucleoside triphosphates (dGTP, dTTP, and dCTP). The present study suggests that, for appropriate agents, pharmacological reduction of deoxynucleoside triphosphate levels represents a potential therapeutic approach for inhibition of HIV-1 replication.
...
PMID:Anti-human immunodeficiency virus type 1 activity of hydroxyurea in combination with 2',3'-dideoxynucleosides. 796 58

Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis--and, consequently, DNA synthesis--by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus-type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages, as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS). The antiviral effect was achieved at nontoxic doses of hydroxyurea, lower than those currently used in human therapy. Combination of hydroxyurea with the nucleoside analog didanosine (2',3'-dideoxyinosine, or ddl) generated a synergistic inhibitory effect without increasing toxicity. In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possible candidate for AIDS therapy.
...
PMID:Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. 797 34

Inhibitors of the ribonucleotide reductase of herpes simplex viruses (HSV) potentiate the activity of acyclovir in vitro and in animal studies. In addition, the combination of the ribonucleotide reductase inhibitor 348U87 and acyclovir has synergistic therapeutic effects against infections in mice due to thymidine kinase-deficient, thymidine kinase-altered, and DNA polymerase mutants of HSV. We performed a pilot study of topical combination therapy with 348U87 (3%) and acyclovir (5%) cream for acyclovir-resistant, anogenital HSV infections in ten human immunodeficiency virus (HIV)-infected patients. Our results, with lack of complete reepitheliazation of lesions in all patients and poor virologic response, suggest that this therapy is unlikely to be useful for this indication.
...
PMID:Potential for combined therapy with 348U87, a ribonucleotide reductase inhibitor, and acyclovir as treatment for acyclovir-resistant herpes simplex virus infection. 824 82

The thiocarbonohydrazone 348U87 inactivates herpes simplex virus ribonucleotide reductase and potentiates the activity of acyclovir against wild-type and acyclovir-resistant strains of herpes simplex virus. We treated 10 human immunodeficiency virus-infected patients with acyclovir-resistant anogenital herpes simplex virus infection with a topical preparation of 348U87 (3%) in combination with acyclovir (5%) in an open-labelled study. Transient improvement with combination therapy occurred frequently; however, target lesions reepithelialized completely in only 1 of 10 patients. Termination of study drug therapy was most often due to cessation of therapeutic effect before complete resolution of lesions. As currently formulated, topical 348U87 offers little therapeutic benefit for this indication.
...
PMID:Topical treatment of infection with acyclovir-resistant mucocutaneous herpes simplex virus with the ribonucleotide reductase inhibitor 348U87 in combination with acyclovir. 839 Aug 15

We studied inhibition of growth of the malaria parasite Plasmodium falciparum in in vitro culture using antisense (AS) oligodeoxynucleotides (ODNs) against different target genes. W2 and W2mef strains of drug-resistant parasites were exposed to AS ODNs over 48 hr, and growth was determined by microscopic examination and [3H]hypoxanthine incorporation. At ODN concentrations of 1 microM, phosphorothioate (PS) ODNs inhibited growth in a target-independent manner. However, between 0.5 and 0.005 microM, ODNs against dihydrofolate reductase, dihydropteroate synthetase, ribonucleotide reductase, the schizont multigene family, and erythrocyte binding antigen EBA175 significantly inhibited growth compared with a PS AS ODN against human immunodeficiency virus, two AS ODNs containing eight mismatches, or the sense strand controls (P < 0.0001). The IC50 was approximately 0.05 microM, whereas that for non-sequence-specific controls was 15-fold higher. PS AS ODNs against DNA polymerase alpha showed less activity than that for other targets, whereas a single AS ODN against triose-phosphate isomerase did not differ significantly from controls. We conclude that at concentrations below 0.5 microM, PS AS ODNs targeted against several malarial genes significantly inhibit growth of drug-resistant parasites in a nucleotide sequence-dependent manner. This technology represents an alternative method for identifying malarial genes as potential drug targets.
...
PMID:Inhibition of Plasmodium falciparum malaria using antisense oligodeoxynucleotides. 855 72

Immunodeficiency in adenosine deaminase deficiency has been attributed to the lymphotoxicity of deoxyadenosine that accumulates to high levels in patients. To gain insight into the mechanism of deoxyadenosine toxicity, we investigated the dose-response and time course of its toxic effects on concanavalin A-stimulated mouse splenic lymphocytes by thymidine incorporation and flow cytometry. Deoxyadenosine at a level as low as 0.3 microM inhibited the progression of G0. In contrast, higher concentrations of the nucleoside, i.e., in the range of 1 to 3 microM, were needed to block transition of the stimulated lymphocytes from G0 to G1. The inhibition of their S entry and progression required even higher concentrations. Furthermore, staurosporine, a potent inhibitor of protein kinases, was found to potentiate the toxicity of deoxyadenosine in mitogen-stimulated lymphocytes. Calcium mobilization in mitogen-activated lymphocytes was inhibited by deoxyadenosine. Our data suggest that, while ribonucleotide reductase inhibition by dATP could explain the blockade of S entry and progression by deoxyadenosine in cycling lymphocytes or leukemic cells, more important effects of this compound on antigen-activated lymphocytes occur at the early G0 phase. A possible mechanism of deoxyadenosine lethality is its inhibition of protein phosphorylation.
...
PMID:Deoxyadenosine blockade of G0 to G1 transition in lymphocytes: possible involvement of protein kinases. 859 88

To assess the efficacy of the therapeutic use of inhibitors of ribonucleotide reductase for the treatment of human immunodeficiency virus (HIV) type 1 infection, 7 consecutive patients were enrolled in a clinical trial involving monotherapy with hydroxyurea for 8-19 weeks. During therapy, patients were evaluated for clinical status and immunologic, hematologic, and quantitative virologic parameters, including determinations of viremia and the number of provirus-containing cells by competitive polymerase chain reaction. In all patients, these parameters were not modified during the course of therapy. The number of CD4 cells remained generally unchanged or showed a tendency to further decline. No sign of improvement in HIV disease was detected in any patient. These observations indicate that monotherapy with hydroxyurea does not provide therapeutic benefit to HIV-1-infected patients.
...
PMID:Treatment of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evaluation. 865 96

Oxidative stress activates the NF-kappaB/Rel transcription factors which are involved in the activation of numerous immunoregulatory genes and the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). In the present study, we examined the effects of established and novel compounds including antioxidants, ribonucleotide reductase inhibitors, and iron chelators on NF-kappaB activation and HIV LTR-mediated gene expression induced by TNF-alpha. N-Acetylcysteine (NAC), pyrrolidinedithiocarbamate (PDTC), and Trimidox (TD) at various concentrations inhibited TNF-alpha-induced NF-kappaB binding in Jurkat cells. Pretreatment of cells with these compounds prior to stimulation prevented I kappaB alpha degradation. Phosphorylation of I kappaB alpha, a prerequisite for its signal-induced degradation, was abrogated in these cells, indicating that oxidative stress is an essential step in the NF-kappaB activation pathway. On the other hand, iron chelators desferrioxamine, pyridoxal isonicotinoyl hydrazone (PIH), and salicylaldehyde isonicotinoyl hydrazone (SIH) showed no inhibition of TNF-alpha-induced NF-kappaB DNA-binding activity. Synergistic induction of HIV-1 LTR-mediated gene expression by TNF-alpha and the HIV-1 transactivator Tat in Jurkat cells was significantly suppressed in the presence of NAC and TD, but not PDTC. The inhibition of NAC and TD on LTR-directed gene expression was diminished when NF-kappaB-binding sites in the LTR were deleted, indicating that these compounds affected the NF-kappaB component of the synergism. Iron chelators PIH and SIH also showed some inhibitory effect on LTR-mediated gene activation, presumably through an NF-kappaB-independent mechanism. These experiments demonstrate that TD, at concentration 50 times lower than the effective concentration of NAC, potently inhibits NF-kappaB activity and suppresses HIV LTR expression.
...
PMID:Selective inhibition of l kappaB alpha phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds. 926 59


<< Previous 1 2 3 4 Next >>

---