Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea has been extensively used in medical practice, mainly for treating chronic myelogenous leukemia, sickle cell anemia, and other diseases. In light of its ability to inhibit DNA synthesis and to induce cell cycle arrest through inhibition of ribonucleotide reductase, the effects of hydroxyurea on replication of human immunodeficiency virus type 1 (HIV-1) have been investigated. In vitro hydroxyurea has been shown to block HIV-1 reverse transcription and/or replication in quiescent peripheral blood mononuclear cells (PBMC) and macrophages. Hydroxyurea was also found to be synergistic with the nucleoside reverse transcriptase inhibitor didanosine and to inhibit HIV-1 replication in activated PBMC; this inhibition may be due to a reduction in deoxynucleoside triphosphate pool sizes. Finally, hydroxyurea has been shown to sensitize didanosine-resistant mutants. Hydroxyurea may therefore be useful for limiting the spread of didanosine-resistant HIV-1 variants. The favorable toxicity profile of hydroxyurea and the lack of significant overlapping toxicities with some of the nucleoside reverse transcriptase inhibitors, as well as their distinct mechanisms of action, have provided further rationale for use of these agents in combination therapies.
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PMID:Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. 1086 Sep 5

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.
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PMID:Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma. 1128 17

Newly publicized trial data are showing that hydroxyurea has strong anti-HIV activity, especially when combined with ddI, which has led to the opening of new trials testing the hydroxyurea/ddI combination. Hydroxyurea's purported mechanism of action against HIV is to inhibit a cellular enzyme, ribonucleotide reductase, that is essential for creating the special nucleotide units needed to form DNA. With fewer natural DNA nucleotides present, HIV's reverse transcriptase enzyme may be more likely to incorporate nucleoside analog compounds, such as AZT or ddI, into the DNA it is creating from HIV's RNA gene template. These nucleoside analogs are defective versions of the natural building blocks and force the viral DNA chain under construction to terminate prematurely. Additional information from various studies and new trials opening in the U.S. and abroad are provided.
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PMID:New data intensifies interest in hydroxyurea. 1136 2

Hydroxyurea, an inhibitor of ribonucleotide reductase in cells, is among the strategies being used to reduce HIV levels. Hydroxyurea disrupts DNA synthesis in rapidly dividing cells and reduces the number of deoxyribonucleotides available to make functional viral products. The combination of hydroxyurea and ddI have shown a positive synergistic effect in reducing HIV viral load. Side effects are influenced by dosage, and include hair loss and bone marrow suppression, making it an inappropriate therapy for people with anemia. Results from completed clinical studies have left unanswered questions on the most appropriate dose of hydroxyurea, who should take it, and when therapy should begin.
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PMID:Hydroxyurea. 1136 34

Hydroxyurea (HU) is an anti-neoplastic agent that may have potential to be used as part of a combination HIV drug regimen. Hydroxyurea seems to make standard antiretroviral drugs more potent and longer acting. It has been used in the past to treat a variety of malignancies and sickle cell anemia, is relatively safe, well tolerated, and inexpensive. The first reports of hydroxyurea's ability to inhibit HIV replication were published in 1994. The drug works by inhibiting ribonucleotide reductase, essential in HIV's ability to produce DNA. Early test results are presented. HU's easy availability and good safety profile make it an attractive addition to HIV combination therapy.
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PMID:Hydroxyurea may enhance effectiveness of anti-HIV regimens presently in use. 1136 24

Hydroxyurea, an inhibitor of DNA synthesis, is used to treat HIV infection. By inhibiting ribonucleotide reductase, hydroxyurea depletes the pool of deoxynucleoside triphosphates, particularly dATP, available for DNA synthesis. Hydroxyurea may be a candidate for use with nucleoside analogs, particularly ddI. Hydroxyurea's use in treating HIV infection with and without ddI, with ddI and without d4T, and with ddI plus a protease inhibitor are discussed. Studies using hydroxyurea with ddI and d4T have shown clinical promise and could be a viable antiretroviral strategy in some patients, especially in countries with limited resources. A regimen containing hydroxyurea, ddI, and a protease inhibitor could be used in aggressive initial or salvage antiretroviral therapy. It is also possible that during acute HIV infection, hydroxyurea's cytostatic properties could contribute to the ultimate preservation of normal immunologic function. Hydroxyurea's dosage level is still uncertain; 500 mg twice daily has been used most often.
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PMID:Hydroxyurea for HIV infection. 1136 49

Three assumptions underlie HIV standard of care decisions: impeding viral reproduction, making treatment regimens manageable so that patients can maintain proper doses, and changing drugs if viral load becomes too high. Brand names, doses, side effects, and drug interactions are included in an overview of nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleotide reverse trascriptase inhibitors, protease inhibitors, and ribonucleotide reductase inhibitors. Nucleoside analogs such as zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC) inhibit an enzyme that the HIV virus needs to dominate cells. Protease inhibitors, such as saquinavir and ritonavir, target a protease enzyme to obstruct HIV from replicating. Ribonucleotide reductase inhibitors, such as hydroxyurea, targets an enzyme made by blood cells. Providers need to be aware of all of the drugs that patients are using to prevent drug resistance and severe drug interactions.
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PMID:HIV treatment options. 1136 4

Published evidence from the U.S. and Europe supports the effect of the anticancer drug hydroxyurea against HIV-1, and its potential synergistic effect with ddl. Approved as an oral chemotherapeutic agent for leukemia and other cancers, hydroxyurea acts as a radical free quencher, inhibiting the cellular enzyme ribonucleotide reductase as well as cellular DNA synthesis during the S phase of the cell division, and it may be through this mechanism that hydroxyurea inhibits tumor cell growth. French scientists at the Centre Leon Bernard in Lyon tested hydroxyurea and a related compound, D-aspartic acid beta-hydroxamate alone and in combination with AZT, ddl, or ddC. Total suppression of viral production and total production against the toxic effects induced by viral replication were demonstrated using the combination of either of the two hydroxamates and ddl after 14 days. In test tube experiments conducted at the National Cancer Institute, both hydroxyurea and ddl inhibited or delayed HIV replication in a dose-dependent manner; in combination, they blocked HIV replication by more than 99.9 percent.
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PMID:Hydroxyurea, a potential new anti-HIV agent. 1136 81

In view of close similarities at the molecular and clinical levels, feline immunodeficiency virus (FIV) infection of the domestic cat is subject of increasing attention as an animal model for human immunodeficiency virus (HIV) infection. A range of reverse transcriptase inhibitors effective against HIV are also active against FIV, allowing successful use of the cat model to investigate drug interactions and resistance development. Nevertheless, while combined nucleoside analog and protease inhibitor usage has proven remarkably effective in treating HIV infection, combination antiretroviral therapy of FIV infection has been hampered by lack of protease inhibitors specific for FIV. In an attempt to circumvent this problem, we have examined the feasibility of applying in the FIV system combination protocols lacking a protease inhibitor. We now report that, as observed during HIV infection, the nucleoside analog abacavir (ABC or 1592U89) is able to effectively block in vitro FIV-replication. Furthermore, we demonstrate that combined usage of ABC with the nucleoside analogs zidovudine (ZDV or AZT) and lamivudine (3TC) also blocks in vitro FIV replication in a synergistic manner. However, in contrast to its effect on HIV replication, the ribonucleotide reductase inhibitor hydroxyurea (HU) is unable to effectively control in vitro FIV replication.
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PMID:Combined effect of zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) antiretroviral therapy in suppressing in vitro FIV replication. 1168 14

Azodicarbonamide tested as an anti-HIV agent was reported to expulse zinc from viral zinc-cysteine factors and to inhibit calcium mobilization machinery. It has structural analogy with hydroxyurea that inhibits ribonucleotide reductase and could also act on this target. Azodicarbonamide was therefore tested for its capacity to modulate deoxyribonucleotides triphosphate pools alone or in combination with other agents in the lymphoblastic SUP-T1 cell line susceptible to HIV infection. The deoxyribonucleotides triphosphate were evaluated by an enzymatic assay using sequenase. Two hours exposure of SUP-T1 cells to 100 microM azodicarbonamide induced a 50% reduction of each deoxyribonucleotide triphosphate. Among other inhibitors of nucleotide metabolism (hydroxyurea, methotrexate and thymidine), hydroxyurea only reproduces the effect of azodicarbonamide. This suggests, but does not demonstrate directly, that azodicarbonamide inhibits ribonucleotide reductase activity. The combination of azodicarbonamide with each of these inhibitors affected particularly the dCTP pool. During this study it was also suggested that azodicarbonamide could interfere with thymidine phosphorylation. Thymidine phosphorylating activity was measured with 3H-thymidine as substrate. In acellular preparations, azodicarbonamide also non-competitively inhibits thymidine phosphorylating activity. This effect was not reproduced by hydroxyurea. Thus, in vitro azodicarbonamide decreases the intracellular pool of deoxyribonucleotide and thymidine phosphorylation.
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PMID:Ribonucleotide reductase and thymidine phosphorylation: two potential targets of azodicarbonamide. 1214 96


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