The Efficacies of Pure LICAM(C) and DTPA on the Retention of Plutonium-238 and Americium-241 in Rats after Their Inhalation as Nitrate and Intravenous Injection as Citrate

Stradling, G.N.; Stather, J.W.; Gray, S.A.; Moody, J.C.; Ellender, M.; Hodgson, Alan; Volf, V.; Taylor, David; Wirth, Philip W.; Gaskin, Paul

doi:10.1080/09553008914551641

Cited by 26 publications

(32 citation statements)

References 14 publications

(16 reference statements)

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“…In baboons that inhaled 239 Pu(IV)-TBP, 10 injections of 30 mol kg Ϫ1 of 3,4,3-LICAM(C) in 28 d reduced bone and liver Pu(IV) more than CaNa 3 -DTPA, but neither ligand influenced lung Pu(IV) (Métivier et al 1985b;Volf 1986;Volf et al 1986;Stradling et al 1986Stradling et al , 1989Gérasimo et al 1986).…”

Section: Catecholate Ligandsmentioning

confidence: 95%

“…The Pu(IV)-3,4,3-LICAM(C) complex formed in the blood at pH 7.4 is unstable at lower pH. It dissociates at the reduced pH of the kidneys depositing Pu(IV), and a stable Pu(IV) chelate may not form in the slightly acidic environment of the lungs (Lloyd et al 1984;Volf 1986;Volf et al 1986;Stradling et al 1986Stradling et al , 1989Durbin et al 1989b). § Significant is used throughout in the statistical sense, based on the t-test (p Յ 0.01, Mack 1967) or other criteria of statistical significance used by individual authors.…”

Section: Catecholate Ligandsmentioning

confidence: 97%

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Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

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All of the actinides are radioactive. Taken into the body, they damage and induce cancer in bone and liver, and in the lungs if inhaled, and U(VI) is a chemical kidney poison. Containment of radionuclides is fundamental to radiation protection, but if it is breached accidentally or deliberately, decontamination of exposed persons is needed to reduce the consequences of radionuclide intake. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents. Ethylendiaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were introduced in the 1950's. DTPA is now clinically accepted, but its oral activity is low, it must be injected as a Ca(II) or Zn(II) chelate to avoid toxicity, and it is structurally unsuitable for chelating U(VI) or Np(V). Actinide penetration into the mammalian iron transport and storage systems suggested that actinide ions would form stable complexes with the Fe(III)-binding units found in potent selective natural iron chelators (siderophores). Testing of that biomimetic approach began in the late 1970's with the design, production, and assessment for in vivo Pu(IV) chelation of synthetic multidentate ligands based on the backbone structures and Fe(III)-binding groups of siderophores. New efficacious actinide chelators have emerged from that program, in particular, octadentate 3,4,3-LI(1,2-HOPO) and tetradentate 5-LIO(Me-3,2-HOPO) have potential for clinical acceptance. Both are much more effective than CaNa3-DTPA for decorporation of Pu(IV), Am(III), U(VI), and Np(IV,V), they are orally active, and toxicity is acceptably low at effective dosage.

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Section: Catecholate Ligandsmentioning

confidence: 95%

Section: Catecholate Ligandsmentioning

confidence: 97%

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Durbin¹

2008

Health Physics

106

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“…..Pu content by solvent extraction and liquid scintillation counting and for their 24 'Am content of measuring the 60 keV emission in a gamma counter. The methodology has been described previously (Stradling et al, 1989a(Stradling et al, , 1991 .…”

Section: 4 Analysis Of Body Tissues and Excretamentioning

confidence: 99%

The Efficacies of 3,4,3-LIHOPO and DTPA for Enhancing the Excretion of Plutonium and Americium from the Rat: Comparison with Other Siderophore Analogues

Stradling¹,

Gray

Ellender

et al. 1992

International Journal of Radiation Biology

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With DTPA as a comparison, the siderophore analogue code named 3,4,3-LIHOPO has been tested for its ability to remove 238Pu and 241Am from rats after their inhalation or intravenous injection as nitrate. The most effective treatment regimen for inhaled Pu was the repeated administration of 30 mumol kg-1 3,4,3-LIHOPO. By 7 days after exposure, the Pu contents of the lungs and total body were reduced respectively to 2 and 4% of those in untreated animals. These values were six and three times less than when DTPA was administered using the same protocol. For inhaled Am, 3,4,3-LIHOPO and DTPA were considered equally effective, the lung and total body contents being reduced respectively to 13 and 10% of those in controls. Some animals showed slight degenerative changes in the liver and proximal tubules of the kidneys after the repeated administration of 30 mumol kg-1 of 3,4,3-LIHOPO; however these changes were less marked than after DTPA treatment. After the intravenous injection of Pu, the most effective regimen was the single administration of 3 mumol kg-1 3,4,3-LIHOPO. The body content at 7 days was reduced to 7% controls compared with 19% after the repeated administration of 30 mumol kg-1 DTPA. At a dosage of 30 mumol kg-1, 3,4,3-LIHOPO was less effective owing to the higher retention of Pu in the liver. With repeated dosages of 30 mumol kg-1 3,4,3-LIHOPO was more effective than DTPA for the decorporation of Am; the body contents were 16 and 31% of those in controls respectively. Importantly, the body content was still reduced to 28% of control after a single administration of 3 mumol kg-1. The ligand 3,4,3-LIHOPO, which is also superior to other siderophore analogues, could represent a most significant development in the decorporation of Pu and Am.

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“…Treatment schedules have been developed and applied to obtain maximal excretion of the radionuclide . The administered dose of the decorporating agent, the route of intake of the radionuclide, the treatment schedule and the time lapse between radioactive contamination and start of the treatment determine significantly the efficacy for the removal of the radionuclides from the body (Volf and Seidel 1974, Guilmette and Muggenburg 1988, Stradling et al . 1989).…”

Section: Introductionmentioning

confidence: 98%

“…Consequently, these tissues are also the sites for cancers induced by radiation (ICRP 1977) . The treatment of choice for decorporation after internal contamination with transportable forms of soluble bone-seeking actinides such as 239 Pu, 24 'Am and 244 Cm is the chelating agent diethylenetriaminepenta-acetic acid (DTPA) (Dolphin 1976, Volf 1978, Stradling et al . 1989) .…”

Section: Introductionmentioning

confidence: 99%

Protracted Treatment of C57B1 Mice with Zn-DTPA after²⁴¹Am Injection Reduces the Long-term Radiation Effects

Schoeters

Maisin

Vanderborght

1991

International Journal of Radiation Biology

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Repeated intraperitoneal injections of ZnNa3-diethylenetriaminepenta-acetate (ZnDTPA), once a week, during 8 successive weeks, and starting 4 days after injection of 58 and 373 kBq 241Am/kg to C57B1 mice, were an effective protection against long-term radiation damage. At both dose levels of 241Am, Zn-DTPA reduced the 241Am concentration in bones by between 33% and 45%, and in the liver by 97%. Mean survival with 241Am was shortened in Zn-DTPA-treated mice, by 17% at the lower dose level and by 70% at the higher dose level. After treatment with DTPA at the lower 241Am level, survival became equal to that of control mice without 241Am, while at the higher level life span was still shortened. After the lower 241Am dose the incidence of bone tumours, liver carcinomas and the total number of all malignant tumours were significantly reduced by chelation therapy. The decrease in bone tumour incidence was proportional to the decrease in 241Am concentration and reduction in cumulative radiation dose in bone after chelation therapy. The incidence of liver carcinomas was reduced to that in non-241Am-injected mice and the reduction was thus proportional to the 97% reduction in 241Am concentration of the liver at the end of chelation therapy. After the higher 241Am dose no tumours showed up in sham-treated mice, probably due to the overkill effect on the cells at risk. In the corresponding Zn-DTPA-treated mice, bone tumours and a few other malignant tumours were observed.

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The Efficacies of Pure LICAM(C) and DTPA on the Retention of Plutonium-238 and Americium-241 in Rats after Their Inhalation as Nitrate and Intravenous Injection as Citrate

Cited by 26 publications

References 14 publications

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

The Efficacies of 3,4,3-LIHOPO and DTPA for Enhancing the Excretion of Plutonium and Americium from the Rat: Comparison with Other Siderophore Analogues

Protracted Treatment of C57B1 Mice with Zn-DTPA after²⁴¹Am Injection Reduces the Long-term Radiation Effects

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The Efficacies of Pure LICAM(C) and DTPA on the Retention of Plutonium-238 and Americium-241 in Rats after Their Inhalation as Nitrate and Intravenous Injection as Citrate

Cited by 26 publications

References 14 publications

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

Lauriston S. Taylor Lecture: The Quest for Therapeutic Actinide Chelators

The Efficacies of 3,4,3-LIHOPO and DTPA for Enhancing the Excretion of Plutonium and Americium from the Rat: Comparison with Other Siderophore Analogues

Protracted Treatment of C57B1 Mice with Zn-DTPA after241Am Injection Reduces the Long-term Radiation Effects

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Protracted Treatment of C57B1 Mice with Zn-DTPA after²⁴¹Am Injection Reduces the Long-term Radiation Effects