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)

This case report is about an eleven year old boy with new developed symptoms of a cellular immundeficiency and a positive HIV-serology 33 months after a CNS-leukemia relapse. After 18 weeks a progredient neurological symptomatology is beginning with motor, cognitive and behavioral disturbances and a brain atrophy in the CT-scan. These cerebral manifestations are explainable as an encephalopathy both through HIV and after CNS-leukemia. A SSPE has been excluded. CT, EEG, Evoked Potentials do not show differential diagnostic pathognomonic findings regarding both diseases. The CSF findings hint at a persistent virus infection compatibel with the postulated slow virus pathogenesis of the AIDS-Encephalopathy. We conclude, that in this case an etiological diagnoses is only possible through histological brain examination and through demonstration of HIV or HIV-antigen in brain tissue respectively. AZT, which is reported to be effective against the cerebral AIDS-manifestations could not be applicated because of the existing pancytopenia.
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PMID:[AIDS encephalopathy in childhood or the late sequela of central nervous system leukemia?]. 316 63

Current thrust in controlling the Acquired Immune Deficiency Syndrome (AIDS) focuses on antiviral drug development targeting the infection and replication of the human immunodeficiency virus (HIV), the causative agent of AIDS. To date, treatment of AIDS has relied on nucleoside reverse transcriptase inhibitors such as AZT, ddI, and ddC, which eventually become ineffective upon the emergence of resistant mutants bearing specific nucleotide substitutions. The Anti-AIDS Drug Screening Program of the NCI conducts and coordinates a high-capacity semi-robotic in vitro screening of synthetic or natural compounds submitted by academic, research and pharmaceutical institutions world-wide. About 10,000 synthetic compounds are screened annually for anti-HIV activity. Confirmed active agents are subjected to in-depth studies on range and mechanism of action. Emerging from this intense screening activity were a number of potentially promising categories of nonnucleoside reverse transcriptase inhibitors (NNRTI) with structural diversity but strong and reproducible anti-HIV activity. Over 2500 active compounds were evaluated for their inhibitory activity against a panel of both laboratory and clinical virus isolates in the appropriate established cell line or fresh human peripheral blood leukocyte and macrophage preparations. Out of these, 40 agents could be placed structurally in nine categories with an additional 16 unique compounds that share the characteristics of NNRTI. These NNRTIs were shown to inhibit reverse transcriptase enzymatically using homopolymeric or ribosomal RNA as templates. NNRTIs demonstrated similarity in their inhibitory pattern against the HIV-1 laboratory strains IIIB and RF, and an AZT-resistant strain; all were inactive against HIV-2. These compounds were further tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1 isolates were selected and characterized with respect to the change(s) in the viral reverse transcriptase nucleotide sequence. Also, differential cross-resistance or sensitivity patterns to NNRTIs were studied in detail among NNRTI-resistant mutants. When tested in combination with AZT, all of the NNRTI's uniformly exhibited synergistic inhibition of HIV-1, suggesting that combination antiviral therapy of NNRTIs with AZT may be therapeutically promising for AIDS treatment.
Leukemia 1995 Oct
PMID:Characteristics of a group of nonnucleoside reverse transcriptase inhibitors with structural diversity and potent anti-human immunodeficiency virus activity. 747 21

R82913 and R86183, two derivatives of tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO), were found to potently and selectively inhibit the replication and cell killing effects of a panel of biologically diverse laboratory and clinical strains of HIV-1. The two compounds exhibited significant activity in all human cell lines tested, as well as in fresh human peripheral blood lymphocytes and macrophages. One of these two compounds (R82913) was found to significantly inhibit the replication of a murine retrovirus (Rauscher murine leukemia virus) in both UV-XC plaque formation and virus yield reduction assays. R86183, despite differing from R82913 only in the positioning of a single chlorine molecule, was not active against the murine retrovirus but was 10-fold more potent in inhibiting HIV-1 replication. Combination antiviral assays with other reverse transcriptase inhibitors, including AZT, ddC, and carbovir, yielded synergistic anti-HIV activity with both TIBO derivatives. Additive to slightly synergistic results were obtained in combinations with ddI and phosphonoformic acid whereas additive to antagonistic activity was detected in combination with dextran sulfate.
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PMID:Differential antiviral activity of two TIBO derivatives against the human immunodeficiency and murine leukemia viruses alone and in combination with other anti-HIV agents. 750 23

A series of benzothiadiazine derivatives were screened against the human immunodeficiency virus (HIV) and certain structure-activity relationships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HIV-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2, and also against both nevirapine- and pyridinone-resistant strains (N119 and A17) of HIV-1, which are cross-resistant to several structurally diverse nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse transcriptase. Combination of NSC 287474 with AZT synergistically inhibited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the simian immunodeficiency virus. The benzothiadiazine class of compounds represents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.
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PMID:Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors. 752 14

Twenty-four specific pathogen-free kittens were infected with the Rickard strain of feline leukemia virus (FeLVR). The kittens were divided into four equal groups and were orally administered either a high dose of diethylcarbamazine (DECH, 12 mg kg-1), a low dose of diethylcarbamazine (DECL, 3 mg kg-1), 3'-azido-3'-deoxythymidine (AZT, 15 mg kg-1, b.i.d.), or a placebo (250 mg granular dextrose) daily for 10 weeks. Blood was collected at 2-week intervals for complete blood counts (CBC) and flow cytometric analysis (FACS) of peripheral blood lymphocytes (PBL). Plasma was assayed for antibodies to FeLV gp70 and for FeLV p27 antigen using ELISA assays. For FACS analysis, lymphocytes were incubated with monoclonal antibodies to feline Pan T, CD8+, CD4+, and B cell (Anti-Ig) antigens. In the placebo treated cats, FeLVR infection caused an early (2 weeks p.i.) and persistent decrease in leukocyte numbers attributable primarily to a decrease in neutrophil numbers and a secondary lesser decrease in B and CD4+ lymphocyte numbers. The DEC-treated groups showed a delayed but similar leukopenia by 4 weeks p.i. The lymphopenia in the DEC groups (primarily B cells and CD4+ cells) was reversed by 10 weeks p.i., but the neutropenia persisted. AZT treatment inhibited FeLVR-induced lymphopenia but did not prevent a reduction in neutrophil numbers. A marked p27 antigenemia that peaked at 4 weeks p.i. was noted in the placebo treated cats and in most cats (11/12) treated with either dose of DEC. However, AZT significantly inhibited the p27 antigenemia and all cats were negative for p27 antigen between 6 and 10 weeks of treatment. In general, placebo treated cats as well as DECH and DECL cats had low levels of antibody to gp70 throughout the study, suggesting FeLVR-induced immunosuppression. In contrast, significantly higher titers of anti-gp70 antibodies were seen in AZT-treated cats at 6 weeks p.i., and were maintained throughout treatment. Eighteen month survival rates provide efficacy data for AZT as well as both DEC treatment groups. While all placebo treated cats were euthanized by 52 weeks p.i. due to FeLV associated lymphomas with a mean survival time of 35.5 weeks p.i., median survival time of the AZT treated group was > or = 102 weeks p.i., while that of the DECH and DECL groups was 69.7 and 72 weeks p.i., respectively. Thus, DEC as well as AZT therapy delays the development of lymphomas associated with FeLV infection and significantly improves survival.
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PMID:Therapeutic effects of diethylcarbamazine and 3'-azido-3'-deoxythymidine on feline leukemia virus lymphoma formation. 894 81

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of human immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse members of a common pharmacologic class of nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase but not HIV-2 reverse transcriptase. Combinations of thiazolobenzimidazole with either AZT or ddI synergistically inhibited HIV-1 induced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolobenzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an enhanced range of anti-retroviral activity.
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PMID:Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. 769 15

During the early stages of human immunodeficiency virus (HIV) infection, although symptoms are absent and viral replication in peripheral blood mononuclear cells is low, substantial levels of HIV replication can be documented in lymphoid tissue [G. Pantaleo, C. Graziosi, J.F. Demarest, L. Butini, M. Montroni, C.H. Fox, J.M. Orenstein, D.P. Kotler, and A.S. Fauci, Nature (London) 362:355-358, 1993, and J. Embretsen, M. Zupancic, J.L. Ribas, A. Burke, P. Racz, K. Tenner-Tacz, and A.T. Haase, Nature (London) 362:359-362, 1993]. This observation suggests that earlier treatment of HIV infection may be indicated and that strategies for enhancing drug targeting to the lymphoid tissue reservoris of HIV infection may be beneficial. To address this issue, we synthesized dioleoylphosphatidyl-ddC (DOP-ddC) and dipalmitoylphosphatidyl-3'-azido-3'-deoxythymidine (DPP-AZT), phospholipid prodrugs which form lipid bilayers and which are readily incorporated into liposomes. The anti-HIV activity of DOP-ddC was similar to that of ddC in HIV type 1-infected HT4-6C cells, but DPP-AZT was considerably less active than AZT in HT4-6C cells. Liposomes containing DOP-[3H]ddC or DPP-[3H]AZT administered intraperitoneally to mice produced greater levels of total radioactivity over time in plasma, spleen, and lymphoid tissue relative to the results with [3H]ddC and [3H]AZT, respectively. DPP-AZT administered intraperitoneally in liposomes as a single daily dose to mice infected with Rauscher leukemia virus prevented increased spleen weight and reverse transcriptase levels in serum with a dose-response roughly comparable to that of AZT given continuously in the drinking water. DOP-ddC, DPP-AZT, and lipid conjugates of other antiretroviral nucleosides may provide higher levels of drug over time in plasma and in lymph nodes and spleen, important reservoirs of HIV infection, and may represent an interesting alternative approach to antiviral nucleoside treatment of AIDS.
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PMID:Phosphatidylazidothymidine and phosphatidyl-ddC: assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in Rauscher leukemia virus-infected mice. 769 64

Perinatal infection of susceptible mice with the neurotropic retrovirus CasBrE leads to a noninflammatory spongiform degeneration of the central nervous system with a long incubation period of up to 1 year. Virus replication in infected animals can be suppressed by administration of antiviral antibodies, cytotoxic T cells, or by AZT treatment, which results in partial to complete protection from neurological disease. A highly neuropathogenic chimeric retrovirus, FrCasE, which contains the envelope gene of CasBrE, induces rapid neurodegeneration within only 16 days. Here we report that this fatal disease could be prevented if a nonneuropathogenic Friend murine leukemia virus was administered to mice prior to their infection with FrCasE. This double inoculation led to a substantial reduction of the replication level of FrCasE in spleen and CNS. Only live but not heat-inactivated nonneuropathogenic virus was able to protect from FrCasE-induced neurological disease. The extent of protection was influenced by the viral envelope gene and the kinetics of replication of the nonneuropathogenic virus. These observations in addition to the rapidity of the effect make it likely that competition for replication sites through the mechanism of viral interference is responsible for the protection. Resistance was demonstrable in vivo even when the "protecting" and "challenge" virus belonged to different in vitro interference groups. However, the protection was considerably weaker than that seen between viruses belonging to the same interference group.
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PMID:Prevention of retrovirus-induced neurological disease by infection with a nonneuropathogenic retrovirus. 783 92

AZT (7.5 or 15 mg/kg/dose) and the neuropeptide methionine enkephalin (Met-ENK, 1 or 3 mg/kg/dose) were used in a combined protocol for therapy of established murine retroviral infection. In both models used, Friend virus leukemia (FV) and BM5 complex (lymphadenopathy and immune deficiency), the drug combination was able to reduce mortality and splenomegaly. While increasing mean survival time of those animals that did not survive infection by FV, when compared to infected control mice or mice treated with AZT alone, Met-ENK used alone at 1 and 3 mg/kg/mouse had no effect in reducing morbidity or mortality due to either virus. This suggested that Met-ENK had no direct antiviral effect at the concentrations used. In fact, mice treated with either single drug therapy or the combination still yielded virus in their spleen, even when splenomegaly was absent. The data suggest that Met-ENK, which has been reported to be immunostimulatory, acts in combination to improve the efficacy of AZT in reducing progression of disease in murine retrovirus models for human AIDS.
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PMID:Methionine enkephalin combined with AZT therapy reduce murine retrovirus-induced disease. 786 96

Combinations of ddC with either the ribonucleotide reductase inhibitor hydroxyurea (HU) or with the natural nucleoside thymidine have been investigated on the cycle of a defective (psi neo) Moloney Leukemia Virus (MoMLV) using 3T3 fibroblasts as host cells. In this experimental model, ddC displayed very poor antiviral action which was obvious given an IC50 value close to 100 microM, i.e. an efficiency about thirty thousand fold lower than that of AZT. Both HU and thymidine alone resulted in significant inhibition of MoMLV replication with IC50 values of 40 microM and 100 microM respectively. The combination of ddC with 50 microM HU lowered the IC50 of ddC by a factor of 10. A similar but more pronounced effect was obtained by combining ddC and 100 microM thymidine, which decreases the IC50 value of ddC by a factor of 50. Combining 40 microM ddC and 100 microM thymidine resulted in the quite complete inhibition of viral replication. These results show that in cell types with strongly restricted ddC action, combination treatment with compounds known to ultimately decrease dCTP biosynthesis leads to the restoration of efficient antiviral activity.
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PMID:Potentiation of 2',3'-dideoxycytidine (ddC) by hydroxyurea and thymidine on the Moloney murine leukemia virus (MoMLV) early replicative steps. 799 21


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