Evidence of Enhanced Iron Excretion During Systemic Phosphorothioate Oligodeoxynucleotide Treatment

Mata, John E.; Bishop, Michael; Tarantolo, Stefano; Angle, Carol R.; Swanson, Stanley A.; Iversen, Patrick L.

doi:10.1081/clt-100100947

Cited by 14 publications

(8 citation statements)

References 12 publications

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“…PS-ONs increase mineral elimination in the urine [ 19 ] and the resulting compensatory response includes liberation of mineral stores (along with heavy metals if present) from the bones into the circulation. All study patients and untreated control subjects at the trial site were shown to have substantial pre-existing heavy metal loads (data not shown) as a result of chronic heavy metal exposure known to be endemic at the trial site [ 20 – 22 ].…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

Al‐Mahtab

Bazinet²,

Vaillant³

2016

PLoS ONE

160

209

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Previous in vivo studies have suggested that nucleic acid polymers (NAPs) may reduce circulating levels of HBsAg in the blood by blocking its release from infected hepatocytes and that this effect may have clinical benefit. NAP treatment, was evaluated in two clinical studies in patients with HBeAg positive chronic HBV infection. The REP 101 study examined REP 2055 monotherapy in 8 patients and the REP 102 study examined REP 2139-Ca, in monotherapy in 12 patients, 9 of which transitioned to short term combined treatment with pegylated interferon alpha 2a or thymosin alpha 1. In both studies NAP monotherapy was accompanied by 2–7 log reductions of serum HBsAg, 3–9 log reductions in serum HBV DNA and the appearance of serum anti-HBsAg antibodies (10–1712 mIU / ml). Eight of the 9 patients transitioning to combined treatment with immunotherapy (pegylated interferon or thymosin alpha 1) in the REP 102 study experienced HBsAg loss and all 9 patients experienced substantial increases in serum anti-HBsAg antibody titers before withdrawal of therapy. For 52 weeks after removal of REP 2055 therapy, rebound of serum viremia (HBV DNA > 1000 copies / ml, HBsAg > 1IU / ml) was not observed in 3 / 8 patients. Suppression of serum virema was further maintained for 290 and 231 weeks in 2 of these patients. After withdrawal of all therapy in the 9 patients that transitioned to combination therapy in the REP 102 study, 8 patients achieved HBV DNA < 116 copies / ml after treatment withdrawal. Viral rebound occurred over a period of 12 to 123 weeks in 7 patients but was still absent in two patients at 135 and 137 weeks of follow-up. Administration tolerability issues observed with REP 2055 were rare with REP 2139-Ca but REP 2139-Ca therapy was accompanied by hair loss, dysphagia and dysgeusia which were considered related to heavy metal exposure endemic at the trial site. These preliminary studies suggest that NAP can elicit important antiviral responses during treatment which may improve the effect of immunotherapy. NAPs may be a potentially useful component of future combination therapies for the treatment of chronic hepatitis B.Trial Registration: ClinicalTrials.gov NCT02646163 and NCT02646189

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

Al‐Mahtab

Bazinet²,

Vaillant³

2016

PLoS ONE

160

209

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“…Intriguingly, the antioxidant effect of phosphorothioate compound showed unexpected selectivity to hydroxyl radical in the anti-oxidant chemistry, compared to traditional antioxidants. It has been postulated that PT “chelator” might coordinate ferrous iron and shut down Fenton reaction 35 . But this seems unlikely in our scenario: first, the in vitro anti-oxidant activity of plasmid DNA was observed even without an iron catalyst (due to difficult manipulation of low concentration H 2 O 2 ); second, the PT consumption was observed at the same level of molar equivalent of H 2 O 2 in the extracted plasmid experiments, indicating that PT is consumable in the anti-oxidant process.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Investigation on ROS Resistance of Phosphorothioated DNA

Huang

Wang

et al. 2017

Sci Rep

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Phosphorothioated DNA (PT-DNA) exhibits a mild anti-oxidant property both in vivo and in vitro. It was found that 8-OHdG and ROS levels were significantly lower in dnd+ (i.e. S+) E. coli., compared to a dnd− (i.e. S−) strain. Furthermore, different from traditional antioxidants, phosphorothioate compound presents an unexpectedly high capacity to quench hydroxyl radical. Oxidative product analysis by liquid chromatography-mass spectrometry and quantum mechanistic computation supported its unique anti-oxidant characteristic of the hydroxyl selectivity: phosphorothioate donates an electron to either hydroxyl radical or guanine radical derived from hydroxyl radical, leading to a PS• radical; a complex of PS• radical and OH− (i.e. the reductive product of hydroxyl radical) releases a highly reductive HS• radical, which scavenges more equivalents of oxidants in the way to high-covalent sulphur compounds such as sulphur, sulphite and sulphate. The PS-PO conversion (PS and PO denote phosphorus-sulphur and phosphorus-oxygen compounds, respectively) made a switch of extremely oxidative OH• to highly reductive HS• species, endowing PT-DNA with the observed high capacity in hydroxyl-radical neutralization. This plausible mechanism provides partial rationale as to why bacteria develop the resource-demanding PT modification on guanine-neighboring phosphates in genome.

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“…The proposed involvement of LIP in the mode in which one FT subunit affects expression of the other 25 was also supported by the fact that the inter-subunit effect was prevented by iron chelators (Figure 4). The possibility that the AS-ODN-mediated repression of FT was evoked by a potential chelating activity of the ODN 42 can be rejected because (1) an ODN containing an identical composition of bases in the reverse order (IN-ODN) produced no repression of FT, (2) FT repression by the AS-ODN was subunit-specific, and (3) LIP was increased, rather than reduced, by the FT-AS-ODN action. Changes in LIP evoked by active down-modulation of FT were also reflected in increased ROS formation and in oxidative modification of cell proteins.…”

Section: Discussionmentioning

confidence: 99%

Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells

Kakhlon

Gruenbaum

Cabantchik

2001

Blood

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The role of ferritin expression on the labile iron pool of cells and its implications for the control of cell proliferation were assessed. Antisense oligodeoxynucleotides were used as tools for modulating the expression of heavy and light ferritin subunits of K562 cells. mRNA and protein levels of each subunit were markedly reduced by 2-day treatment with antisense probes against the respective subunit. Although the combined action of antisense probes against both subunits reduced their protein expression, antisense repression of one subunit led to an increased protein expression of the other. Antisense treatment led to a rise in the steady-state labile iron pool, a rise in the production of reactive oxygen species after pro-oxidative challenges and in protein oxidation, and the down-regulation of transferrin receptors. When compared to the repression of individual subunits, corepression of each subunit evoked a more than additive increase in the labile iron pool and the extent of protein oxidation. These treatments had no detectable effects on the long-term growth of cells.

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Evidence of Enhanced Iron Excretion During Systemic Phosphorothioate Oligodeoxynucleotide Treatment

Cited by 14 publications

References 12 publications

Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection

Mechanistic Investigation on ROS Resistance of Phosphorothioated DNA

Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells

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