Ribonucleotide Reductase Inhibitor

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Howard L. Elford - One of the best experts on this subject based on the ideXlab platform.

  • molecular targeting of rrm2 nf κb and mutant tp53 for the treatment of triple negative breast cancer
    Molecular Cancer Therapeutics, 2021
    Co-Authors: Elizabeth A Wilson, Howard L. Elford, Khyati N. Shah, Nahid Sultana, Jesika S. Faridi
    Abstract:

    Doxorubicin and other anthracycline derivatives are frequently used as part of the adjuvant chemotherapy regimen for triple-negative breast cancer (TNBC). Although effective, doxorubicin is known for its off-target and toxic side effect profile, particularly with respect to the myocardium, often resulting in left ventricular (LV) dysfunction and congestive heart failure when used at cumulative doses exceeding 400 mg/m2. Previously, we have observed that the Ribonucleotide Reductase subunit M2 (RRM2) is significantly overexpressed in estrogen receptor (ER)–negative cells as compared with ER-positive breast cancer cells. Here, we inhibited RRM2 in ER-negative breast cancer cells as a target for therapy in this difficult-to-treat population. We observed that through the use of didox, a Ribonucleotide Reductase Inhibitor, the reduction in RRM2 was accompanied by reduced NF-κB activity in vitro. When didox was used in combination with doxorubicin, we observed significant downregulation of NF-κB proteins accompanied by reduced TNBC cell proliferation. As well, we observed that protein levels of mutant p53 were significantly reduced by didox or combination therapy in vitro. Xenograft studies showed that combination therapy was found to be synergistic in vivo, resulting in a significantly reduced tumor volume as compared with doxorubicin monotherapy. In addition, the use of didox was also found to ameliorate the toxic myocardial effects of doxorubicin in vivo as measured by heart mass, LV diameter, and serum troponin T levels. The data present a novel and promising approach for the treatment of TNBC that merits further clinical evaluation in humans.

  • The Ribonucleotide Reductase Inhibitor, Didox, Reduces the In Vivo Vascular Inflammation and Oxidative Stress Induced By Acute Hemolysis
    Blood, 2018
    Co-Authors: Nicola Conran, Howard L. Elford, Juliete A.f. Silva, Erica M.f. Gotardo, Hanan Chweih, Lediana I. Miguel, Flavia C. Leonardo, Wilson A. Ferreira, Bo E. Hedlund, Fernando F. Costa
    Abstract:

    Introduction: Several diseases and disorders, including hereditary and acquired hemolytic anemia, blood transfusion reactions, preeclampsia and some infections, incur intravascular hemolysis to varying degrees. The destruction of red blood cells and the release of hemoglobin (Hb) and heme into the circulation results in vascular inflammation, characterized by the recruitment of leukocytes to the vascular endothelium, reduced nitric oxide bioavailability and oxidative stress, all of which may contribute to complications seen in hemolytic diseases, such as pulmonary hypertension, cutaneous leg ulcers and priapism. Didox (3,4-dihydroxybenzohydroxamic acid), a Ribonucleotide Reductase Inhibitor, has been shown to have anti-inflammatory and anti-oxidative effects. This molecule has potential as a cancer therapy and has demonstrated beneficial effects in numerous pathologies, diminishing vaso-occlusive processes in mice with sickle cell disease, and suppressing mast cell activation and degranulation, amongst other effects. Aims: The aim of this study was to evaluate the effects of didox on the vascular inflammatory effects of in vivo acute hemolysis. Methods: C57BL/6 mice received i.v. didox (10 mg/animal) or the same volume of saline vehicle immediately before receiving the hemolytic stimulus. In some mice, didox (10 mg) was given intraperitonally (i.p.) 30 min before hemolysis. Acute hemolysis (HEM) was induced by injecting mice (i.v.) with 100 µl sterile water; for non-hemolysis controls (CON), the same quantity of saline was administered i.v.. At 15 min post-hemolysis, blood was obtained by cardiac puncture for biochemical and flow cytometry analyses; other animals were submitted to cremaster muscle exposure followed by intravital microscopy. Results: Intravascular H2O administration successfully induced hemolysis within 15 min, as demonstrated by elevated plasma cell-free Hb and heme levels (plasma Hb: 0.20±0.05 and 0.66±0.16 mg/ml, P Disclosures Elford:Molecules for Health, Inc.: Equity Ownership, Patents & Royalties: Didox.

  • The efficacy of the Ribonucleotide Reductase Inhibitor Didox in preclinical models of AML.
    PLoS ONE, 2014
    Co-Authors: Guerry J Cook, Howard L. Elford, David L. Caudell, Timothy S. Pardee
    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.

  • Abstract 4227: The Ribonucleotide Reductase Inhibitor Didox reverses tamoxifen resistance in breast cancer cells
    Molecular and Cellular Biology, 2014
    Co-Authors: Khyati N. Shah, Howard L. Elford, Jesika S. Faridi
    Abstract:

    Tamoxifen is the most prescribed endocrine therapy for estrogen receptor positive breast cancer patients. The emergence of endocrine resistance is a major hurdle in achieving a successful clinical outcome. Many advances have been made over the past few years to understand the biology of tamoxifen resistance. Activation of the AKT kinase is one of the primary mechanisms of intrinsic tamoxifen resistance. Previously, we reported that the Ribonucleotide Reductase M2 (RRM2) subunit is upregulated in AKT induced tamoxifen resistance and that inhibition of RRM2 by siRNA mediated interference reduces tamoxifen induced cell proliferation. In this study, we report that the inhibition of RRM2 by the small molecule Inhibitor of Ribonucleotide Reductase activity Didox (3, 4-dihydroxybenzohydroxamic acid), significantly reduced tamoxifen induced cell proliferation in AKT overexpressing cells and tamoxifen resistant tumors generated by these cells. As well, Didox in combination with tamoxifen also inhibited cell proliferation in acquired tamoxifen resistant breast cancer cell lines. Employing comprehensive cell culture and in vivo models, we demonstrate that combining tamoxifen with Didox may reverse tamoxifen resistance in AKT expressing breast cancer cells. Citation Format: Khyati N. Shah, Howard L. Elford, Jesika S. Faridi. The Ribonucleotide Reductase Inhibitor Didox reverses tamoxifen resistance in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4227. doi:10.1158/1538-7445.AM2014-4227

  • The Novel Ribonucleotide Reductase Inhibitor Didox Is Active Against AML with Limited Toxicities
    Blood, 2012
    Co-Authors: Guerry J Cook, Howard L. Elford, David L. Caudell, Timothy S. Pardee
    Abstract:

    Abstract 1513 Acute myeloid leukemia (AML) is an aggressive, genetically heterogeneous malignancy wherein immature progenitors crowd out the normal hematopoietic cells, leading to marrow failure and death. In 2013, it is projected that there will be 13,780 new cases and 10,200 deaths from AML in the United States. Even with decades of research into this disease, treatments remain unchanged and patient survival dismal. Standard treatment for AML is combination chemotherapy with cytarabine and an anthracycline. Treatment will often lead to a remission; however, most patients relapse with chemoresistant disease. This highlights the need for the development of new therapies. Ribonucleotide Reductase (RR) facilitates the rate-limiting reaction in DNA synthesis. Hydroxyurea (HU) is a well-known Inhibitor of RR, resulting in the depletion of purine nucleotides. It has a role in AML as a cytoreductive agent and in the palliative setting, where other regimens have been deemed too intensive. However, its myelosuppressive and GI toxicities are dose-limiting. Didox is an Inhibitor of RR, which inhibits both purine and pyrimidine synthesis, and has been shown to be less myelosuppressive than HU. In our previous studies in a panel of human AML cell lines, Didox had an average IC 50 of 5.76 μM (range 3.62–7.37 μM). To evaluate if Didox treatment resulted in DNA damage we assessed γH2AX foci formation in KG1a cells. After a 24-hour exposure to a titration of Didox nuclei were scored for the presence of γH2AX foci. Didox induced DNA damage in this erythroleukemia cell line at 24 hours, with a mean score of 0.480 in the negative control, 0.852 with 5 μM, 0.907 with 10 μM, and 0.976 at 20 μM Didox (p=0.0015 by 1-way ANOVA). Consistent with Didox exposure resulting in DNA damage, we saw induction of p53 in OCI/AML3 cells by Western blot following Didox treatment. To determine if Didox exposure culminated in induction of apoptosis, we performed an annexin V/propidium iodide assay. Didox induced apoptosis in KG1a cells (45.27% positive compared to 3.15% positivity in the negative control). To determine the effect of Didox on leukemic progenitor cells we exposed KG1a cells to a titration of Didox for 24 hours and then performed a colony formation assay. Didox reduced the colony-forming potential of KG1a cells (5% at 200nM, 21.9% at 2μM, 60.6% at 20 μM, and 84.3% reduction at 200 μM). These data demonstrate that Didox is an active agent which inhibits RR resulting in DNA damage, p53 induction and culminating in cell death via apoptosis. Previous in vivo studies carried out in syngeneic, therapy-resistant MLL-ENL-driven AML models (one expressing Flt3 ITD and one over-expressing NRas G12D ) yielded a reduction in leukemic burden (p= 0.0342 and 0.0026, respectively) and a survival benefit (p= 0.0094 and 0.0001, respectively) with a five-day Didox treatment at 425 mg/kg/d compared to vehicle-treated controls. We evaluated the impact of Didox given in this fashion on normal progenitors by treating normal 8-week-old C57Bl/6. 72 hours post-treatment, the animals were sacrificed and the bone marrow, sternum, and small intestine (SI) were harvested for toxicity studies. The sternum and SI from the Didox and control-treated samples were reviewed by a veterinary pathologist blinded to the treatment group. No differences were observed between Didox treated and control groups. To determine if Didox exposure affected the activity of normal hematopoietic stem cells bone marrow was harvested from treated mice and injected into Ly5.1+ secondary recipients. After 21 days recipient mice were sacrificed, bone marrow harvested, and evaluated for engraftment. Preliminary data suggested that Didox treatment did not alter engraftment potential of normal progenitors (Didox treated bone marrow 87.44% versus control marrow 89.75% engraftment). Didox is a RR Inhibitor with activity in models of AML. Our in vitro data indicate that Didox is active against leukemic progenitor cells with reduced colony-formation potential of treated cells. Furthermore, at the effective dose, Didox was not toxic to normal tissues. Most importantly, preliminary data suggests it does not alter the engraftment potential of normal hematopoietic cells. The activity of Didox combined with its favorable toxicity profile makes it an ideal candidate for further translation to the clinic. Disclosures: Elford: Molecules for Health: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees.

L Corey - One of the best experts on this subject based on the ideXlab platform.

Mario Sznol - One of the best experts on this subject based on the ideXlab platform.

  • a phase i study of the novel Ribonucleotide Reductase Inhibitor 3 aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap triapine in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myelopr
    Leukemia Research, 2008
    Co-Authors: Judith E. Karp, Ivana Gojo, Jacqueline Greer, Francis J. Giles, Bonny Johnson, Mario Sznol, Lawrence E Morris, Mya Thein, Jennifer Low
    Abstract:

    Abstract Triapine ® is a potent Ribonucleotide Reductase (RR) Inhibitor that depletes intracellular deoxyribonculeotide pools, especially dATP. We designed a Phase I trial of Triapine followed by the adenosine analog fludarabine in adults with refractory acute leukemias and aggressive myeloproliferative disorders (MPD). Two schedules were examined: (A) Triapine 105 mg/m 2 /day over 4 h followed by fludarabine daily × 5 (24 patients, fludarabine 15–30 mg/m 2 /dose); (B) Triapine 200 mg/m 2 over 24 h followed by 5 days of fludarabine 30 mg/m 2 /day (9 patients). Complete and partial responses (CR, PR) occurred in Schedule A (5/24, 21%), with CR occurring at the 2 highest fludarabine doses (2/12, 17%). In contrast, no CR or PR occurred in Schedule B. Four of the 5 responses occurred in patients with underlying MPD (4/14, 29%). Drug-related toxicities included fever and metabolic acidosis. Triapine 105 mg/m 2 followed by fludarabine 30 mg/m2 daily × 5 is active in refractory myeloid malignancies and warrants continuing study for patients with aggressive MPD.

  • phase i and pharmacokinetic study of triapine a potent Ribonucleotide Reductase Inhibitor in adults with advanced hematologic malignancies
    Leukemia Research, 2007
    Co-Authors: Ivana Gojo, Jacqueline Greer, Michael L Tidwell, Naoko Takebe, Karen Seiter, Mary F Pochron, Bonny Johnson, Mario Sznol, Judith E. Karp
    Abstract:

    Abstract Triapine®, a potent Inhibitor of Ribonucleotide Reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1–5 and 15–19 or 1–5 and 8–12 of a 4-week cycle. When administered twice a day on days 1–5 and 8–12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2–5.5 μM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.

  • phase i and pharmacokinetic study of the Ribonucleotide Reductase Inhibitor 3 aminopyridine 2 carboxaldehyde thiosemicarbazone administered by 96 hour intravenous continuous infusion
    Journal of Clinical Oncology, 2004
    Co-Authors: Scott Wadler, Della Makower, Caroline Clairmont, Paula Lambert, Karen Fehn, Mario Sznol
    Abstract:

    Purpose 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent Inhibitor of Ribonucleotide Reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer. Patients and Methods Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients. Results Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m2/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m2/d but administered eve...

  • phase i and pharmacokinetic study of triapine a potent Ribonucleotide Reductase Inhibitor administered daily for five days in patients with advanced solid tumors
    Clinical Cancer Research, 2003
    Co-Authors: Caroline Clairmont, Paula Lambert, John R Murren, Manuel R Modiano, Niramol Savaraj, Terry Doyle, Mario Sznol
    Abstract:

    Purpose: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule Inhibitor of Ribonucleotide Reductase. Experimental Design: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m2/day, but was reduced to 2 mg/m2/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3–6 patients. After the 12 mg/m2/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m2/day, the study was amended to determine the safety and tolerability of the 96-mg/m2 dose administered daily for 5 days every 2 weeks in an expanded cohort of patients. Results: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2–4 drug-related adverse events were first observed at a dose of 96 mg/m2/day. Grade 3–4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m2 dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1–2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3–4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m2/day dose averaged 8 μm, and the mean elimination T 1/2 ranged from 35 min to 3 h, with a median value of ∼1 h. Cumulative urinary recovery averaged 1–3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed. Conclusions: Triapine administered at a dose of 96 mg/m2 by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-Inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of Ribonucleotide Reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.

S Safrin - One of the best experts on this subject based on the ideXlab platform.

Robert Deziel - One of the best experts on this subject based on the ideXlab platform.

  • antiviral activity of a selective Ribonucleotide Reductase Inhibitor against acyclovir resistant herpes simplex virus type 1 in vivo
    Antimicrobial Agents and Chemotherapy, 1998
    Co-Authors: Jianmin Duan, Michel Liuzzi, William Paris, Michelle Lambert, Carol Lawetz, Neil Moss, Jorge Jaramillo, Jean Gauthier, Robert Deziel, Michael G Cordingley
    Abstract:

    The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (nu/nu) mice. BILD 1633 SE is a novel peptidomimetic Inhibitor of HSV Ribonucleotide Reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAAr5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5 infections. The effect of BILD 1633 SE against HSV-1 PAAr5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 10(6) and 10(7) PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1 dlsptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk and PAAr5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association Inhibitor can be effective against ACV-resistant HSV infections in vivo.

  • evaluation of a peptidomimetic Ribonucleotide Reductase Inhibitor with a murine model of herpes simplex virus type 1 ocular disease
    Antimicrobial Agents and Chemotherapy, 1996
    Co-Authors: Curtis R Brandt, Brian Spencer, Pascal D Imesch, M Garneau, Robert Deziel
    Abstract:

    The Ribonucleotide Reductase (RR) of herpes simplex virus type 1 (HSV-1) is an important virulence factor, being required for neurovirulence, ocular virulence, and reactivation from latency. The RR activity requires the association of two distinct homodimeric subunits, and the association of the subunits is inhibited in the presence of a peptide homologous to the carboxy terminus of the small subunit. A structural analog of the Inhibitory peptide (BILD 1263) has been shown to inhibit the replication of HSV-1 at micromolar concentrations in vitro. We used a mouse model of HSV-1 ocular infection to determine the in vivo efficacy of topical BILD 1263. Treatment of HSV-1 KOS-infected mice resulted in significant reductions in the severity and incidence of stromal keratitis and corneal neovascularization. At higher concentrations (5%) BILD 1263 reduced the severity but not the incidence of blepharitis. Treatment with 5% BILD 1263 also reduced viral shedding from the cornea by 10- to 14-fold (P < 0.001). In uninfected mice treated with 5% BILD 1263, we found no evidence of corneal epithelial damage, conjunctivitis, or blepharitis, and histopathological studies revealed no changes in the corneas of these mice. These results show that the peptidomimetic RR Inhibitor BILD 1263 is effective in preventing disease, has an antiviral effect in vivo, and has little or no toxicity.

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