28 results on '"Elford HL"'
Search Results
2. Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription.
- Author
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McLeod JJA, Caslin HL, Spence AJ, Kolawole EM, Qayum AA, Paranjape A, Taruselli M, Haque TT, Kiwanuka KN, Elford HL, and Ryan JJ
- Subjects
- Acetylcysteine pharmacology, Animals, Bone Marrow Cells immunology, Catalase biosynthesis, Cell Degranulation drug effects, Cells, Cultured, Chemokine CCL3 biosynthesis, Hypersensitivity immunology, Interleukin-13 biosynthesis, Interleukin-6 biosynthesis, Mast Cells drug effects, Mice, Mice, Inbred C57BL, Oxidative Stress drug effects, Oxidative Stress immunology, Reactive Oxygen Species metabolism, Superoxide Dismutase biosynthesis, Transcription, Genetic drug effects, Tumor Necrosis Factor-alpha biosynthesis, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Hydroxamic Acids pharmacology, Hypersensitivity drug therapy, Immunoglobulin E immunology, Mast Cells immunology, NF-kappa B genetics, Transcription Factor AP-1 genetics
- Abstract
Mast cell activation via the high-affinity IgE receptor (FcεRI) elicits production of inflammatory mediators central to allergic disease. As a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor, Didox (3,4-dihyroxybenzohydroxamic acid) has been tested in clinical trials for cancer and is an attractive therapeutic for inflammatory disease. We found that Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3). These effects were consistent using BMMC of different genetic backgrounds and peritoneal mast cells. While the RNR inhibitor hydroxyurea had little or no effect on IgE-mediated function, high concentrations of the antioxidant N-acetylcysteine mimicked Didox-mediated suppression. Furthermore, Didox increased expression of the antioxidant genes superoxide dismutase and catalase, and suppressed DCFH-DA fluorescence, indicating reduced reactive oxygen species production. Didox effects were not due to changes in FcεRI expression or cell viability, suggesting it inhibits signaling required for inflammatory cytokine production. In support of this, we found that Didox reduced FcεRI-mediated AP-1 and NFκB transcriptional activity. Finally, Didox suppressed mast cell-dependent, IgE-mediated passive systemic anaphylaxis in vivo. These data demonstrate the potential use for Didox asa means of antagonizing mast cell responses in allergic disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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3. Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells.
- Author
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Caslin HL, McLeod JJA, Spence AJ, Qayum AA, Kolawole EM, Taruselli MT, Paranjape A, Elford HL, and Ryan JJ
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- Acetylcysteine pharmacology, Animals, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, Chemokine CCL3 antagonists & inhibitors, Chemokine CCL3 genetics, Chemokine CCL3 immunology, Female, Gene Expression Regulation immunology, Genes, Reporter, Hydroxyurea pharmacology, Interleukin-13 antagonists & inhibitors, Interleukin-13 genetics, Interleukin-13 immunology, Interleukin-33 antagonists & inhibitors, Lipopolysaccharides pharmacology, Luciferases genetics, Luciferases immunology, Male, Mast Cells cytology, Mast Cells immunology, Mice, Mice, Inbred C57BL, NF-kappa B antagonists & inhibitors, NF-kappa B genetics, NF-kappa B immunology, Primary Cell Culture, Signal Transduction, Transcription Factor AP-1 antagonists & inhibitors, Transcription Factor AP-1 genetics, Transcription Factor AP-1 immunology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Gene Expression Regulation drug effects, Hydroxamic Acids pharmacology, Immunosuppressive Agents pharmacology, Interleukin-33 pharmacology, Mast Cells drug effects
- Abstract
While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation. This suppression was observed in different genetic backgrounds and extended to peritoneal mast cells. The antioxidant N-acetylcysteine mimicked the suppression of Didox, albeit at a much higher dose, while the RNR inhibitor hydroxyurea had no effect. Didox substantially suppressed IL-33-mediated NFκB and AP-1 transcriptional activities. These results suggest that Didox attenuates IL-33-induced mast cell activation and should be further studied as a potential therapeutic agent for inflammatory diseases involving IL-33., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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4. Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer.
- Author
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Shah KN, Wilson EA, Malla R, Elford HL, and Faridi JS
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- Animals, Antineoplastic Agents pharmacology, Blotting, Western, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Movement drug effects, Cell Movement genetics, Cell Proliferation drug effects, Cell Proliferation genetics, Drug Synergism, ErbB Receptors metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Humans, Kaplan-Meier Estimate, MCF-7 Cells, Mice, Nude, NF-kappa B metabolism, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleoside Diphosphate Reductase genetics, Ribonucleoside Diphosphate Reductase metabolism, Signal Transduction drug effects, Xenograft Model Antitumor Assays, Breast Neoplasms drug therapy, Drug Resistance, Neoplasm drug effects, Hydroxamic Acids pharmacology, NF-kappa B antagonists & inhibitors, Ribonucleoside Diphosphate Reductase antagonists & inhibitors, Tamoxifen pharmacology
- Abstract
Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERα)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERα66 and upregulation of the 36-kDa variant of ER (ERα36). We identified that NF-κB, HIF1α, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-κB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-κB activation, combining didox with tamoxifen treatment cooperatively reverses ER-α alterations and inhibits NF-κB activation. Finally, inhibition of RRM2 by didox reversed tamoxifen-resistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance., (©2015 American Association for Cancer Research.)
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- 2015
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5. The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML.
- Author
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Cook GJ, Caudell DL, Elford HL, and Pardee TS
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- Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Apoptosis drug effects, DNA Damage drug effects, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Enzyme Inhibitors administration & dosage, Female, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Hydroxamic Acids administration & dosage, Karyotype, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Male, Mice, Mice, Inbred C57BL, Middle Aged, Ribonucleotide Reductases antagonists & inhibitors, Signal Transduction drug effects, Tumor Stem Cell Assay, Tumor Suppressor Protein p53 metabolism, Enzyme Inhibitors pharmacology, Hydroxamic Acids pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89-52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML.
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- 2014
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6. Ribonucleotide reductase inhibitors reduce atherosclerosis in a double-injury rabbit model.
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Gallaugher LD, Henry JC, Kearns PN, Elford HL, Bergdall VK, and Cardounel AJ
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- Animals, Rabbits, Atherosclerosis prevention & control, Disease Models, Animal, Enzyme Inhibitors pharmacology, Hydroxamic Acids pharmacology, Hydroxyurea pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Atheroproliferative disorders such as atherosclerosis are an important health problem and one of the leading causes of morbidity and mortality in the United States. Minimally invasive therapeutic procedures, including angioplasty with stent deployment, are used frequently for obstructive coronary artery disease. However, restenosis, a proliferative vascular response, is a common sequela to this procedure. The current study investigated the effect of inhibiting ribonucleotide reductase (RR), an enzyme necessary for cellular proliferation, in an attempt to ameliorate the proliferative response. Two RR inhibitors, didox and hydroxyurea, were chosen for their potent antiproliferative properties. Studies were carried out by using a double-injury rabbit model, in which endothelial denudation was followed by the administration of a high-fat diet. At 4 wk after initial endothelial denudation, the developing atherosclerotic lesion was subjected to transluminal balloon dilation to simulate clinical intervention with percutaneous transluminal angioplasty. The degree of restenosis and atheroproliferation was assessed at 8 wk. Histologic evaluation of the lesion demonstrated that treatment with didox and hydroxyurea significantly decreased lesion area and lumen loss. These results suggest that RR inhibition may be an effective new tool for the treatment of atheroproliferative disorders.
- Published
- 2009
7. Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells.
- Author
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Raje N, Kumar S, Hideshima T, Ishitsuka K, Yasui H, Chhetri S, Vallet S, Vonescu E, Shiraishi N, Kiziltepe T, Elford HL, Munshi NC, and Anderson KC
- Subjects
- Antineoplastic Agents, Alkylating pharmacology, Caspases physiology, Cell Cycle drug effects, Cell Survival drug effects, DNA Repair genetics, Dose-Response Relationship, Drug, Down-Regulation drug effects, Drug Evaluation, Preclinical, Drug Synergism, Enzyme Inhibitors pharmacology, Gene Expression Regulation, Neoplastic drug effects, Humans, Melphalan pharmacology, Multiple Myeloma genetics, Multiple Myeloma metabolism, Neoplasm Proteins metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Ribonucleotide Reductases antagonists & inhibitors, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, DNA Repair drug effects, Hydroxamic Acids pharmacology, Multiple Myeloma pathology
- Abstract
Ribonucleotide reductase (RR) is the enzyme that catalyses the rate-limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti-myeloma activity of Didox (3,4-Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase-dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2.0 gene chip. Specifically, a >or=2-fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl-2, bcl(xl), and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0.7 as determined by the Chou-Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA-damaging agents, to improve patient outcome in MM.
- Published
- 2006
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8. Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.
- Author
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Mayhew CN, Sumpter R, Inayat M, Cibull M, Phillips JD, Elford HL, and Gallicchio VS
- Subjects
- Animals, Antiviral Agents administration & dosage, B-Lymphocytes immunology, Benzamidines administration & dosage, Drug Therapy, Combination, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors therapeutic use, Female, Hydroxamic Acids administration & dosage, Hydroxyurea administration & dosage, Leukemia Virus, Murine drug effects, Leukemia, Experimental drug therapy, Leukemia, Experimental virology, Lymphocyte Activation drug effects, Mice, Mice, Inbred C57BL, Murine Acquired Immunodeficiency Syndrome virology, Retroviridae Infections drug therapy, Retroviridae Infections virology, Ribonucleotide Reductases antagonists & inhibitors, Treatment Outcome, Tumor Virus Infections drug therapy, Tumor Virus Infections virology, Antiviral Agents therapeutic use, Benzamidines therapeutic use, Didanosine therapeutic use, Hydroxamic Acids therapeutic use, Hydroxyurea therapeutic use, Murine Acquired Immunodeficiency Syndrome drug therapy, Reverse Transcriptase Inhibitors therapeutic use
- Abstract
The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.
- Published
- 2005
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9. Synergistic cytotoxicity of the ribonucleotide reductase inhibitor didox (3,4-dihydroxy-benzohydroxamic acid) and the alkylating agent carmustine (BCNU) in 9L rat gliosarcoma cells and DAOY human medulloblastoma cells.
- Author
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Horvath Z, Höchtl T, Bauer W, Fritzer-Szekeres M, Elford HL, Szekeres T, and Tihan T
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- Animals, Drug Interactions, Humans, Rats, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Antineoplastic Agents toxicity, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Alkylating toxicity, Brain Neoplasms pathology, Carmustine pharmacology, Carmustine toxicity, Cerebellar Neoplasms pathology, Gliosarcoma pathology, Hydroxamic Acids pharmacology, Hydroxamic Acids toxicity, Medulloblastoma pathology
- Abstract
Purpose: Ribonucleotide reductase (RR) is the rate-limiting enzyme of de novo DNA synthesis and has been shown to be upregulated linked with proliferation and malignant transformation. It was therefore identified as an excellent target for antitumor therapy. In the present study we investigated the biochemical and cytotoxic effects of didox, an inhibitor of RR, as a single agent and in combination with BCNU, an alkylating anticancer drug, in 9L rat gliosarcoma cells and DAOY human medulloblastoma cells., Methods: The effect of didox on the intracellular concentrations of deoxynucleosidetriphosphates (dNTPs) was studied in 9L cells. Pool sizes were determined by HPLC. In addition, the cytotoxic effects of didox and BCNU as single drugs and in equimolar combination were tested in 9L and in DAOY cells. Combination effects were determined according to the equation of Chou and Talalay. The expression of DNA repair-related genes was determined after exposure of 9L cells to BCNU, didox and a combination of the two compounds, using a cDNA array., Results: Incubation of 9L cells with 30 microM didox for 24 h significantly decreased the intracellular concentrations of the DNA precursors dCTP (61% of control) and dGTP (17% of control), and significantly increased the concentration of dATP (155% of control). This dNTP imbalance compromised DNA synthesis and repair and might therefore have been, at least in part, responsible for the highly synergistic cytotoxic effects seen when BCNU was used simultaneously with didox in 9L and in DAOY cells. With almost all combinations tested, highly synergistic effects were seen, as indicated by combination indices of <1 according to the equation of Chou and Talalay. In 9L cells, BCNU upregulated the expression of DNA repair-associated genes, whereas coincubation of the cells with didox reduced overexpression of some of these repair-related genes., Conclusion: A combination of BCNU and didox was proven to act in a synergistic manner in two cell lines, 9L rat gliosarcoma and DAOY human medulloblastoma cells. Further in vivo tests using these two compounds systemically and/or locally at the tumor site might be warranted.
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- 2004
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10. Suppression of retrovirus-induced immunodeficiency disease (murine AIDS) by trimidox and didox: novel ribonucleotide reductase inhibitors with less bone marrow toxicity than hydroxyurea.
- Author
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Mayhew CN, Mampuru LJ, Chendil D, Ahmed MM, Phillips JD, Greenberg RN, Elford HL, and Gallicchio VS
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- Animals, Benzamidines chemistry, Benzamidines therapeutic use, DNA, Viral, Female, Femur cytology, Femur drug effects, Free Radical Scavengers chemistry, Free Radical Scavengers therapeutic use, Hematopoietic Stem Cells drug effects, Hydroxamic Acids chemistry, Hydroxamic Acids therapeutic use, Hydroxyurea chemistry, Hydroxyurea therapeutic use, Hypergammaglobulinemia drug therapy, Leukemia Virus, Murine genetics, Leukemia, Experimental blood, Leukemia, Experimental drug therapy, Leukemia, Experimental immunology, Mice, Mice, Inbred C57BL, Murine Acquired Immunodeficiency Syndrome blood, Murine Acquired Immunodeficiency Syndrome drug therapy, Murine Acquired Immunodeficiency Syndrome immunology, Proviruses genetics, Retroviridae Infections blood, Retroviridae Infections drug therapy, Retroviridae Infections immunology, Spleen pathology, Splenomegaly, Tumor Virus Infections blood, Tumor Virus Infections drug therapy, Tumor Virus Infections immunology, Benzamidines adverse effects, Bone Marrow Cells drug effects, Free Radical Scavengers adverse effects, Hydroxamic Acids adverse effects, Hydroxyurea adverse effects, Leukemia Virus, Murine drug effects, Leukemia, Experimental pathology, Murine Acquired Immunodeficiency Syndrome pathology, Retroviridae Infections pathology, Ribonucleotide Reductases antagonists & inhibitors, Tumor Virus Infections pathology
- Abstract
Recently, the use of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) in combination with nucleoside analogs has gained attention as a potential strategy for anti-HIV-1 therapy. However, appeal for the long-term use of HU in HIV-1 infection may be limited by its propensity to induce hematopoietic toxicity. We report a comparison of the efficacy and bone marrow toxicity of HU (400 and 200 mg/kg/day) with the novel RR inhibitors and free radical-scavenging compounds didox (DX; 3,4-dihydroxybenzohydroxamic acid; 350 mg/kg/day) and trimidox (TX; 3,4,5-trihydroxybenzamidoxime; 175 mg/kg/day) in the murine AIDS (LPBM5 MuLV) model of retrovirus infection. Infected mice received daily drug treatment for 8 weeks. Efficacy was determined by measuring drug effects on retroviral-induced disease progression (i.e. development of splenomegaly and hypergammaglobulinemia) and by evaluating splenic levels of proviral DNA. Bone marrow toxicity was evaluated by measuring peripheral blood indices (WBC, hematocrit and reticulocyte counts), femoral cellularity and by determining the numbers of hematopoietic progenitor cells (CFU-GM, BFU-E) per femur and spleen. Compared to infected controls receiving no drug treatment, disease progression was significantly suppressed by TX, DX and HU. However, HU was associated with mortality and induced significant hematopoietic toxicity in a time- and dose-dependent manner. Conversely, TX and DX effectively inhibited retrovirus-induced disease but did not induce hematopoietic toxicity. These results suggest that due to their reduced hematopoietic toxicity and ability to inhibit disease progression in murine AIDS, TX and DX may offer effective alternatives to HU therapy in HIV-1 infection., (Copyright 2002 Elsevier Science B.V.)
- Published
- 2002
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11. Short-term treatment with novel ribonucleotide reductase inhibitors Trimidox and Didox reverses late-stage murine retrovirus-induced lymphoproliferative disease with less bone marrow toxicity than hydroxyurea.
- Author
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Mayhew CN, Phillips JD, Cibull ML, Elford HL, and Gallicchio VS
- Subjects
- Animals, Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, Benzamidines administration & dosage, Benzamidines adverse effects, Blood Cell Count, Body Weight drug effects, Bone Marrow pathology, Hydroxamic Acids administration & dosage, Hydroxamic Acids adverse effects, Hydroxyurea therapeutic use, Lymphoproliferative Disorders pathology, Lymphoproliferative Disorders virology, Mice, Spleen drug effects, Spleen pathology, Time Factors, Antiviral Agents adverse effects, Benzamidines therapeutic use, Bone Marrow drug effects, Hydroxamic Acids therapeutic use, Hydroxyurea adverse effects, Leukemia Virus, Murine physiology, Lymphoproliferative Disorders drug therapy
- Abstract
We evaluated the ability of a short course of treatment with the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) and two novel RR inhibitors Trimidox (TX) and Didox (DX) to influence late-stage murine retrovirus-induced lymphoproliferative disease. LPBM5 murine leukaemia virus retrovirus-infected mice were treated daily with HU, TX or DX for 4 weeks, beginning 9 weeks post-infection, after development of immunodeficiency and lymphoproliferative disease. Drug effects on disease progression were determined by evaluating spleen weight and histology. Effects on haematopoiesis were determined by measuring peripheral blood indices (white blood cells and haematocrit) and assay of femur cellularity and femoral and splenic content of colony-forming units granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). HU, TX and DX partially reversed late-stage retrovirus-induced disease, resulting in spleen weights significantly below pre-treatment values. Spleen histology was also improved by RR inhibitor treatment (DX>TX>HU). However, as expected, HU was significantly myelosuppressive, inducing a reduction in peripheral indices associated with depletion of femoral CFU-GM and BFU-E. In contrast, although TX and DX were moderately myelosuppressive, both drugs were significantly better tolerated than HU. In summary, short-term treatment in late-stage murine retroviral disease with HU, TX or DX induced dramatic reversal of disease pathophysiology. However, the novel RR inhibitors TX and DX had more effective activity and significantly less bone marrow toxicity than HU.
- Published
- 2002
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12. Didox (a novel ribonucleotide reductase inhibitor) overcomes Bcl-2 mediated radiation resistance in prostate cancer cell line PC-3.
- Author
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Inayat MS, Chendil D, Mohiuddin M, Elford HL, Gallicchio VS, and Ahmed MM
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- Apoptosis radiation effects, Cell Line, Cell Survival radiation effects, Combined Modality Therapy, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Gene Expression Regulation, Neoplastic radiation effects, Genetic Vectors, Humans, Male, Mitosis drug effects, Mitosis radiation effects, NF-kappa B drug effects, NF-kappa B radiation effects, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins drug effects, Proto-Oncogene Proteins radiation effects, Proto-Oncogene Proteins c-bcl-2 radiation effects, Radiation, Ionizing, Transfection, Tumor Cells, Cultured, bcl-2-Associated X Protein, Antineoplastic Agents therapeutic use, Hydroxamic Acids therapeutic use, Prostatic Neoplasms radiotherapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Radiation Tolerance
- Abstract
In this study, we investigated the influence of Bcl-2 overexpression on the radiosensitizing potential of Didox (DX; 3,4-Dihydroxybenzohydroxamic acid), a novel ribonucleotide reductase inhibitor, in p53-null prostate cancer cell line PC-3. The PC-3 cells were transfected with vector alone or ectopically overexpressed with CMV-Bcl-2 construct. The effect of radiation (IR) or DX alone and in combination (pre and post IR exposure of DX) on cell survival was determined by colony-forming assay. The impact of these two treatments on the cell cycle was determined by flow cytometry. To further understand the molecular mechanism of DX-mediated radiosensitization, induction of pro-survival and pro-apoptotic factors were determined by Western blot and gel-shift assays respectively. When compared to PC-3/Bcl-2 cells (SF(2)=0.84; D(0)=437cGy), the PC-3/vector cells (SF(2)=0.4; D(0)=235cGy) were significantly sensitive to ionizing radiation (p<0.001). Exposure of DX at 5 microM concentration prior or post to radiation in both PC-3/vector and PC-3/Bcl-2 transfectants caused an increase in radiation enhancement ratios. A significant reduction in G(2)M phase was observed in cells exposed to DX post IR when compared to cells exposed to IR alone. Exposure to DX after radiation in PC-3/vector significantly abrogated radiation-induced Bcl-2 upregulation, with a concomitant induction of bax protein. In PC-3/Bcl-2 transfectants, DX exposure after IR caused an induction of bax protein. Gel shift assays indicated that in PC-3/vector cells when exposed to IR caused an induction of NFkappa-B activity however, DX down regulated the NFkappa-B activity. Radiation-induced NFkappa-B activity was abrogated in pre and post DX exposure in combination with IR. These findings indicate that DX mediates a potent radiosensitizing effect in p53 null prostate cancer cells by overcoming radiation induced NFkappa-B activity and Bcl-2 expression.
- Published
- 2002
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13. Activation of caspases and induction of apoptosis by novel ribonucleotide reductase inhibitors amidox and didox.
- Author
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Grusch M, Fritzer-Szekeres M, Fuhrmann G, Rosenberger G, Luxbacher C, Elford HL, Smid K, Peters GJ, Szekeres T, and Krupitza G
- Subjects
- Annexin A5 metabolism, Caspase 8, Caspase 9, DNA Fragmentation, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Gelsolin metabolism, HL-60 Cells drug effects, HL-60 Cells enzymology, Humans, K562 Cells drug effects, K562 Cells enzymology, Phosphatidylserines metabolism, Pilot Projects, Poly(ADP-ribose) Polymerases metabolism, Apoptosis drug effects, Caspase Inhibitors, Caspases drug effects, Enzyme Inhibitors pharmacology, Hydroxamic Acids pharmacology, Neoplasm Proteins antagonists & inhibitors, Oximes pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Objective: Amidox and didox are two polyhydroxy-substituted benzohydroxamic acid derivatives that belong to a new class of ribonucleotide reductase (RR) inhibitors. RR is the rate-limiting enzyme for de novo deoxyribonucleotide synthesis, and its activity is significantly increased in tumor cells in proportion to the proliferation rate. Therefore, RR is a target for antitumor therapy., Materials and Methods: HL-60 and K562 leukemia cells were treated with increasing doses of amidox and didox. Thereafter, the mode of cytotoxic drug action was determined by Hoechst 33258/propidium iodide (HO/PI) double staining, annexin binding, DNA fragmentation, and caspase activation. This was correlated to the decrease in dNTP levels. Staining with HO/PI and binding of fluorescein isothiocyanate-conjugated annexin V to externalized phosphatidylserine were used to quantify apoptosis., Results: Low doses of amidox or didox resulted in an increase of apoptotic HL-60 cells within 48 hours. Higher doses (50 microM amidox or 250 microM didox) led to rapid induction of apoptosis, which could be detected as early as 4 hours after treatment. After 48 hours with these concentrations, almost 100% of the HL-60 cells died by apoptosis without an increase in necrosis. K562 cells were found to be resistant to amidox but not to didox. In HL-60 cells, upstream caspase 8 is processed in response to didox, whereas caspases 8 and 9 are processed upon amidox treatment. Didox-induced apoptosis, but not amidox-induced apoptosis, can be correlated with the decrease in dNTP levels. The results suggests that amidox induces several apoptosis mechanisms in HL-60 cells. In contrast, only caspase 9 is activated by didox in K562 cells, and because amidox hardly induces apoptosis in this cell line, no caspase cleavage is observed., Conclusions: Didox triggers distinct apoptosis pathways in HL-60 and K562 cells.
- Published
- 2001
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14. Enhancement of hemoglobin and F-cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (didox and trimidox) in combination with streptozotocin.
- Author
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Iyamu WE, Adunyah SE, Fasold H, Horiuchi K, Elford HL, Asakura T, and Turner EA
- Subjects
- Antineoplastic Agents therapeutic use, Benzamidines therapeutic use, Cell Differentiation drug effects, Cell Division drug effects, Drug Therapy, Combination, Humans, Hydroxamic Acids therapeutic use, K562 Cells metabolism, Ribonucleotide Reductases antagonists & inhibitors, Benzamidines pharmacology, Enzyme Inhibitors pharmacology, Fetal Hemoglobin biosynthesis, Hemoglobin, Sickle biosynthesis, Hydroxamic Acids pharmacology, K562 Cells cytology, Streptozocin therapeutic use
- Abstract
Upon appropriate drug treatment, the human erythroleukemic K562 cells have been shown to produce hemoglobin and F-cells. Fetal hemoglobin (Hb F) inhibits the polymerization events of sickle hemoglobin (Hb S), thereby ameliorating the clinical symptoms of sickle cell disease. Ribonucleotide reductase inhibitors (RRIs) have been shown to inhibit the growth of myeloid leukemia cells leading to the production of Hb F upon differentiation. Of the RRIs currently in use, hydroxyurea is the most effective agent for Hb F induction. We have examined the capacity of two novel RRIs, didox (DI) and trimidox (TRI), in combination with streptozotocin (STZ), to induce hemoglobin and F-cell production. The K562 cells were cultured with different concentrations of didox-STZ or trimidox-STZ at a fixed molar ratio of 3:1 and 1:5 for 96 hr, respectively. At pre-determined time intervals, aliquots of cells were obtained and total hemoglobin (benzidine positive) levels, number of F-cells, and Hb F were determined by the differential staining technique, fetal hemoglobin assay kit, and fluorescence cytometry respectively. The effect of combined drug treatment on the growth of K562 cells was examined by isobologram analysis. Our results indicate that a synergistic growth-inhibitory differentiation effect occurred when didox or trimidox was used in combination with STZ on K562 cells. There was an increase in the number of both benzidine-positive normoblasts and F-cells, accompanied by morphologic appearances typical of erythroid maturation. On day 4, the number of benzidine-positive cells showed a 6-9-fold increase and the number of F-cells was between 2.5- and 5.7-fold higher than the respective controls. Based upon these results, treatment with a ribonucleotide reductase inhibitor, such as didox or trimidox, in combination with STZ, might offer an additional promising option in sickle cell disease therapy., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
- Full Text
- View/download PDF
15. In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-HIV-1 activity.
- Author
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Mayhew CN, Phillips JD, Greenberg RN, Birch NJ, Elford HL, and Gallicchio VS
- Subjects
- Acquired Immunodeficiency Syndrome drug therapy, Anemia chemically induced, Animals, Cells, Cultured, Colony-Forming Units Assay, Female, Femur, Hematopoiesis drug effects, Humans, In Vitro Techniques, Lymphocytes cytology, Lymphocytes drug effects, Macrophages cytology, Macrophages drug effects, Mice, Mice, Inbred C57BL, Neutrophils cytology, Neutrophils drug effects, Organ Size, Spleen cytology, Anti-HIV Agents toxicity, Benzamidines toxicity, Enzyme Inhibitors toxicity, Hematopoietic Stem Cells drug effects, Hydroxamic Acids toxicity, Hydroxyurea toxicity, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [HU]) have been proposed as a new therapeutic strategy for the treatment of HIV type-1 (HIV-1) infection. However, HU use may be limited by the frequent development of hematopoietic toxicity. We report here short-term hematopoietic toxicity in mice receiving HU when compared to either of two more potent enzyme inhibitors, didox (DX) and trimidox (TX). High dose HU, DX, and TX monotherapy (500, 460, and 220 mg/kg/day respectively) was administered by daily i.p. injection (Monday-Friday) to C57BL/6 mice for 10 weeks. Effects on hematopoiesis were established by quantitating peripheral blood indices (hematocrit, hemoglobin, mean corpuscular volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, RBC, and WBC) and numbers of colony-forming units-granulocyte-macrophage (CFU-GM) and BFU-E from bone marrow and spleen. HU produced rapid induction of a macrocytic hypochromic anemia and altered white blood cell kinetics associated with myelosuppression defined as reduced marrow organ cellularity and induction of splenic extramedullary hematopoiesis. Compared to HU, TX and DX induced fewer changes in peripheral blood indices and CFU-GM and BFU-E per hematopoietic organ. In vitro human and murine marrow CFU-GM and BFU-E colony formations were assayed in the presence of dose escalation HU, DX, or TX (0, 1, 10, 50, 100, and 200 microM). HU inhibited colony formation more than either DX or TX. These in vivo and in vitro studies suggest that novel ribonucleotide reductase inhibitors TX and DX may provide an effective alternative to HU in HIV-1 therapy because they demonstrate reduced hematopoietic toxicity.
- Published
- 1999
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- View/download PDF
16. Antimalarial activities of polyhydroxyphenyl and hydroxamic acid derivatives.
- Author
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Holland KP, Elford HL, Bracchi V, Annis CG, Schuster SM, and Chakrabarti D
- Subjects
- Animals, Hydroxyurea pharmacology, Plasmodium falciparum drug effects, Structure-Activity Relationship, Antimalarials pharmacology, Hydroxamic Acids pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Several known mammalian ribonucleotide reductase inhibitors featuring a polyhydroxyphenyl and/or hydroxamate moiety as the active group were screened for potency in inhibiting growth of the malaria parasite Plasmodium falciparum. Compounds containing a 2,3- or 3,4-dihydroxyphenyl group as well as benzohydroxamate appear to be the most effective inhibitors of the malaria parasite.
- Published
- 1998
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- View/download PDF
17. Iron binding capacity of didox (3,4 dihydroxybenzohydroxamic acid) and amidox (3,4 dihydroxybenzamidoxime) two inhibitors of the enzyme ribonucleotide reductase.
- Author
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Fritzer-Szekeres M, Novotny L, Vachalkova A, Göbl R, Elford HL, and Szekeres T
- Subjects
- Animals, Antineoplastic Agents toxicity, Cell Division drug effects, Enzyme Inhibitors toxicity, Humans, Hydroxamic Acids toxicity, Iron pharmacology, Leukemia L1210, Mice, Oximes toxicity, Polarography, Tumor Cells, Cultured, Antineoplastic Agents chemistry, Enzyme Inhibitors chemistry, Hydroxamic Acids chemistry, Iron chemistry, Oximes chemistry, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Ribonucleotide reductase is the rate limiting enzyme of deoxynucleoside triphosphate synthesis and is considered to be an excellent target of cancer chemotherapy. Didox and amidox are newly synthesized compounds, which inhibit this enzyme and have in vitro and in vivo antitumor activity. We have now investigated the capability of didox and amidox to interfere with the iron metabolism. We show by photometric and polarographic methods, that didox and amidox are capable of forming an iron complex. However, their cytotoxic action cannot be circumvented by addition of Fe-ammoniumcitrate, indicating the iron complexing capacity not to be responsible for the mechanism of action of these compounds. When L1210 leukemia cells were incubated with the didox-iron or amidox-iron complex itself, only slight changes of the 50% growth inhibitory capacity of the complex in comparison with didox or amidox alone could be shown. We conclude, that didox and amidox are capable of forming an iron complex, but in contrast to other agents, the anticancer activity cannot be contributed to this effect alone. Further studies will have to elucidate the molecular mechanism of action of these new and promising anticancer agents.
- Published
- 1998
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18. The new inhibitors of ribonucleotide reductase--comparison of some physico-chemical properties.
- Author
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Romanova D, Vachalkova A, Szekeres T, Elford HL, and Novotny L
- Subjects
- Benzamidines pharmacology, Chromatography, High Pressure Liquid, Enzyme Inhibitors pharmacology, Hydrogen-Ion Concentration, Hydroxamic Acids pharmacology, Oximes pharmacology, Polarography, Spectrophotometry, Ultraviolet, Benzamidines chemistry, Enzyme Inhibitors chemistry, Hydroxamic Acids chemistry, Oximes chemistry, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Amidox (AX), didox (DX) and trimidox (TX), compounds synthetized as new ribonucleotide reductase inhibitors, have been investigated by ultraviolet (UV) spectrophotometry, polarography and high performance liquid chromatography (HPLC). The experiments have been performed at various pH values. The changes in UV absorption of the compounds studied were recorded and it was demonstrated that these changes are related to the pH and to structural features of the investigated molecules. From the compounds included in our series of experiments, only amidox and trimidox are reduced during polarographic experiments in Britton-Robinson buffer. The reduction of both compounds proceeded in two one-electron steps in acidic pH. One two-electron diffuse irreversible wave was observed at basic pH. The values of the half-wave potential became more negative in accordance with the increasing pH. HPLC assay also showed changes in the retention of compounds investigated, particularly when the pH of the mobile phase was close to the dissociation constant of the particular drug. The changes of physico-chemical properties detected by the all used methods are related to different chemical structures (the most significant changes were observed in alkaline pH).
- Published
- 1997
- Full Text
- View/download PDF
19. Iron binding capacity of didox (3,4-dihydroxybenzohydroxamic acid) and amidox (3,4-dihydroxybenzamidoxime) new inhibitors of the enzyme ribonucleotide reductase.
- Author
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Fritzer-Szekeres M, Novotny L, Vachalkova A, Findenig G, Elford HL, and Szekeres T
- Subjects
- Animals, Antineoplastic Agents toxicity, Enzyme Inhibitors toxicity, Humans, Hydroxamic Acids toxicity, Leukemia L1210 drug therapy, Leukemia, Erythroblastic, Acute drug therapy, Mice, Oxidation-Reduction, Oximes toxicity, Polarography, Tumor Cells, Cultured, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Hydroxamic Acids metabolism, Hydroxamic Acids pharmacology, Iron Compounds metabolism, Oximes metabolism, Oximes pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Ribonucleotide reductase is the rate limiting enzyme of deoxynucleoside triphosphate synthesis and is considered to be an excellent target of cancer chemotherapy. Didox and amidox are newly synthesized compounds, which inhibit this enzyme and have in vitro and in vivo antitumor activity. We have now investigated the capability of didox and amidox to interfere with the iron metabolism. We show by photometric and polarographic methods, that didox and amidox are capable of forming an iron complex. However, their cytotoxic action cannot be completely circumvented by addition of Fe-ammoniumcitrate, indicating that the iron complexing capacity may not be responsible for the mechanism of action of these compounds. When L1210 leukemia cells were incubated with the didox-iron or amidox-iron complex itself, changes of the 50% growth inhibitory capacity of the complex in comparison with didox or amidox alone could be shown. We conclude, that didox and amidox are capable of forming iron complexes, but in contrast to other agents, the anticancer activity cannot be contributed to this effect alone. Future studies will have to elucidate the molecular mechanism of action of these new and promising anticancer agents.
- Published
- 1997
- Full Text
- View/download PDF
20. Transgenic mouse model of pharmacologic induction of fetal hemoglobin: studies using a new ribonucleotide reductase inhibitor, Didox.
- Author
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Pace BS, Elford HL, and Stamatoyannopoulos G
- Subjects
- Anemia chemically induced, Animals, Chemical and Drug Induced Liver Injury, Erythropoietin therapeutic use, Gene Expression drug effects, Humans, Hydroxamic Acids adverse effects, Hydroxamic Acids toxicity, Leukopenia chemically induced, Mice, Mice, Transgenic, Recombinant Proteins therapeutic use, Reticulocytes metabolism, Thrombocytopenia chemically induced, Fetal Hemoglobin biosynthesis, Hydroxamic Acids pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Evaluation of pharmacologic agents that stimulate fetal hemoglobin production has been done mainly in baboons and macaques. We investigated whether results in transgenic mice can predict the stimulation of fetal hemoglobin in primates, by testing gamma globin induction in response to a new ribonucleotide reductase inhibitor, Didox. A transgenic mouse line carrying the human A gamma gene linked to a locus control region cassette was used. Treatment of transgenic mice with Didox resulted in induction of gamma gene expression as documented by an increase in F reticulocytes and F cells and an elevation of gamma/gamma + beta biosynthetic ratio. Similarly, administration of Didox to a baboon in the nonanemic and chronically anemic state resulted in induction of gamma gene expression as shown by increases in F reticulocytes, F cells, and Hb F. These results suggest that the muLCR-A gamma transgenic mice can be used to screen new pharmacologic compounds for gamma globin inducibility.
- Published
- 1994
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21. Studies on the mechanisms of inhibition of L1210 cell growth by 3,4-dihydroxybenzohydroxamic acid and 3,4-dihydroxybenzamidoxime.
- Author
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Tihan T, Elford HL, and Cory JG
- Subjects
- Animals, Cell Line, Cytidine metabolism, Deoxyribonucleotides metabolism, Hydroxyurea pharmacology, Kinetics, Mice, Antineoplastic Agents pharmacology, Cell Division drug effects, Hydroxamic Acids pharmacology, Leukemia L1210 metabolism, Oximes pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Didox and Amidox inhibit L1210 cell growth in culture. At least one of the mechanisms in the mode(s) of action of the compounds is directed at the ribonucleotide reductase site. Partially purified preparations of ribonucleotide reductase activity are inhibited by Amidox and Didox. The formation of deoxycytidine nucleotides from [14C]cytidine in intact L1210 cells is also blocked. Didox and Amidox cause the decrease in the intracellular pools of the four dNTPs. Hydroxyurea-resistant L1210 cells are not cross-resistant to either Didox or Amidox. These data suggest that Didox and Amidox are not inhibiting ribonucleotide reductase through a mechanism similar to hydroxyurea.
- Published
- 1991
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22. A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.
- Author
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Carmichael J, Cantwell BM, Mannix KA, Veale D, Elford HL, Blackie R, Kerr DJ, Kaye SB, and Harris AL
- Subjects
- Adult, Aged, Drug Administration Schedule, Drug Evaluation, Female, Humans, Hydroxamic Acids adverse effects, Hydroxamic Acids pharmacokinetics, Infusions, Intravenous, Male, Middle Aged, Hydroxamic Acids administration & dosage, Neoplasms drug therapy, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m-2, above which dose-limiting hepatic toxicity was observed. Patient tolerance was significantly better using the 36 h infusion compared to patients receiving the drug by a 30 min infusion; in particular, there were no reports of nausea or vomiting. No responses were seen in these patients. Detailed pharmacokinetics were performed at 6 g m-2 comparing the 36 h and 30 min infusions in four patients. Parent drug AUC values were lower for the 36 h infusion, 67.8 micrograms ml-1 h-1 compared to 232 micrograms ml-1 h-1 for the 30 min infusion. AUC values for the 3-hydroxy metabolite were much higher following the 36 h infusion: 55.4 compared to 18.6 micrograms ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 micrograms ml-1 h-1 were seen after the 30 min infusion. The mean peak plasma level was 72 micrograms ml-1 following 6 g m-2 given by a 30 min infusion compared to 2.8 micrograms ml-1 following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1.
- Published
- 1990
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23. Modulation of cytarabine metabolism in the human promyelocytic leukemia cell line HL-60 by polyhydroxy-substituted benzohydroxamic acids.
- Author
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Howell SB, Gill S, and Elford HL
- Subjects
- Cell Line, DNA metabolism, Humans, Time Factors, Cytarabine metabolism, Hydroxamic Acids pharmacology, Leukemia, Myeloid metabolism
- Abstract
Two potent new ribonucleotide reductase inhibitors, 3,4,5-trihydroxybenzohydroxamic acid (VF 122) and 3,4-dihydroxybenzohydroxamic acid (VF 147), were investigated for their ability to modulate the cellular pharmacology of cytarabine (ara-C) in HL-60 cells. VF 122 and VF 147 increased the total cellular uptake of ara-C by a mean (+/- SE) of 8% +/- 3% and 29% +/- 3%, respectively, when measured 2 hours after the start of exposure to 0.1 microM ara-C. This effect was evident after only 10 minutes of exposure to the riboNucleotide reductase inhibitor and did not vary significantly over the concentration range of 10-100 microM for either agent. VF 122 enhanced the incorporation of ara-CTP into DNA by 3.6-fold; VF 147 produced a 5.6-fold increase. In comparison, the maximum enhancement achievable with hydroxyurea was 2.1-fold, and with thymidine was 1.8-fold. These results provide a biochemical rationale for further investigation of these agents in combination with ara-C.
- Published
- 1982
24. Structure-activity relationships of benzohydroxamic acid inhibitors of ribonucleotide reductase.
- Author
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van't Riet B, Kier LB, and Elford HL
- Subjects
- Chemical Phenomena, Chemistry, Hydroxamic Acids chemical synthesis, Structure-Activity Relationship, Hydroxamic Acids pharmacology, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
A structure-activity relationship study of 28 substituted benzohydroxamic acids that inhibit ribonucleotide reductase was undertaken to discern the structural features of the molecule contributing to the inhibitory potency of these compounds. An equation containing three molecular connectivity indexes, but not including Hammett sigma values, was developed which gives close correlation with observed values for ribonucleotide reductase inhibition. It is postulated that the inhibitory potency involves two parts of the benzohydroxamic acid molecule. One is the hydroxamic portion, which complexes with the metal component of the enzyme, providing a qualitative effect. The other is an interaction involving the benzene ring and its substituents and may provide the quantitative aspect of the observed inhibition values.
- Published
- 1980
- Full Text
- View/download PDF
25. Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.
- Author
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van't Riet B, Wampler GL, and Elford HL
- Subjects
- Animals, Dose-Response Relationship, Drug, Female, Hydroxamic Acids pharmacology, Hydroxamic Acids therapeutic use, Hydroxyurea therapeutic use, In Vitro Techniques, Leukemia L1210 drug therapy, Liver Neoplasms, Experimental enzymology, Mice, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Hydroxamic Acids chemical synthesis, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.
- Published
- 1979
- Full Text
- View/download PDF
26. Inhibition of nucleoside diphosphate reductase by hydroxybenzohydroxamic acid derivatives.
- Author
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Elford HL and van't Riet B
- Subjects
- Animals, Basidiomycota analysis, Deoxyribonucleotides metabolism, Dihydroxyphenylalanine pharmacology, Drug Synergism, HeLa Cells, Humans, Neoplasms, Experimental drug therapy, Antineoplastic Agents pharmacology, Hydroxamic Acids pharmacology, Phenols pharmacology, Ribonucleoside Diphosphate Reductase antagonists & inhibitors, Ribonucleotide Reductases antagonists & inhibitors
- Published
- 1985
- Full Text
- View/download PDF
27. A phase 1 and pharmacokinetic study of didox: a ribonucleotide reductase inhibitor.
- Author
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Veale D, Carmichael J, Cantwell BM, Elford HL, Blackie R, Kerr DJ, Kaye SB, and Harris AL
- Subjects
- Adult, Aged, Drug Evaluation, Female, Humans, Hydroxamic Acids adverse effects, Hydroxamic Acids pharmacokinetics, Liver Function Tests, Male, Middle Aged, Nausea chemically induced, Neoplasm Metastasis, Neoplasms blood, Urination Disorders chemically induced, Vomiting chemically induced, Hydroxamic Acids therapeutic use, Neoplasms drug therapy, Ribonucleotide Reductases antagonists & inhibitors
- Abstract
A phase 1 study of a new ribonucleotide reductase inhibitor, didox, was performed by administration of escalating doses of the drug by slow i.v. injection. Thirty-four patients with unresponsive metastatic carcinoma received the drug. There were 13 escalations of dosage, from a starting dose of 192 mg m-2 to 10 g m-2. Dose limiting toxicity was encountered at 7.5 g m-2 where disturbances of hepatic and renal function were observed, in addition to severe gastrointestinal toxicity. Pharmacokinetic studies showed that a peak level of didox was achieved within 5 minutes of injection. At 1,728 mg m-2 the data best fitted a 2 compartment open model, with a mean serum alpha t1/2 of 5.2 min, with a beta t1/2 of 41.3 min. Less than 10% of the drug was excreted unchanged in the urine and the majority of this excretion was within 6 h. Didox can therefore be safely given by slow i.v. injection at a dose of 6 g m-2.
- Published
- 1988
- Full Text
- View/download PDF
28. New ribonucleotide reductase inhibitors with antineoplastic activity.
- Author
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Elford HL, Wampler GL, and van't Riet B
- Subjects
- Animals, Female, Hydroxyurea pharmacology, Mice, Mice, Inbred Strains, Structure-Activity Relationship, Antineoplastic Agents, Hydroxamic Acids pharmacology, Leukemia L1210 drug therapy, Ribonucleotide Reductases antagonists & inhibitors
- Published
- 1979
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