title: Dose-dependent efficacy and safety toxicology of hydroxypyridinonate actinide decorporation agents in rodents: towards a safe and effective human dosing regimen.
abstract: Two hydroxypyridinone-containing actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Dose-response efficacy profiles in mice were established for the removal of intravenously injected (238)Pu and (241)Am after parenteral and oral treatment with these chelators. In both cases, presumed efficacious doses promoted substantially greater actinide elimination rates than the currently approved agent, diethylenetriamine-pentaacetic acid, considering two different interspecies scaling methods for the conversion of human doses to equivalent rodent dose levels. In addition, genotoxicity of both ligands was assessed using the Salmonella/ Escherichia coli /microsome plate incorporation test and the Chinese hamster ovary cell chromosome aberration assay, showing that neither ligand is genotoxic, in the presence and absence of metabolic activation. Finally, maximum tolerated dose studies were performed in rats for seven consecutive daily oral administrations with the chelators, confirming the safety of the presumed efficacious doses for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). The results of these studies add to the growing body of evidence that both decorporation agents have remarkable decorporation efficacy properties and promising safety toxicology profiles. These results are necessary components of the regulatory approval process and will help determine the optimal human dosing regimens for the treatment of internal radionuclide contamination.
authors.affiliation: Biosciences Division, SRI International, Menlo Park, California 94025M, USA.
authors.forename: Deborah I
authors.initials: DI
authors.lastname: Bunin
authors.forename: Polly Y
authors.initials: PY
authors.lastname: Chang
authors.forename: Rupa S
authors.initials: RS
authors.lastname: Doppalapudi
authors.forename: Edward S
authors.initials: ES
authors.lastname: Riccio
authors.forename: Dahlia
authors.initials: D
authors.lastname: An
authors.forename: Erin E
authors.initials: EE
authors.lastname: Jarvis
authors.forename: Birgitta
authors.initials: B
authors.lastname: Kullgren
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Abergel
mesh_terms: D000576:Americium / Q000737:chemistry*; D000818:Animals; D024201:Bystander Effect / Q000187:drug effects; D016466:CHO Cells; D002614:Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D009152:Mutagenicity Tests; D009154:Mutation; D011005:Plutonium / Q000737:chemistry*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012449:Safety; D015398:Signal Transduction / Q000187:drug effects; D018675:Toxicity Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D002614:Chelating Agents; D011728:Pyridones; D016159:Tumor Suppressor Protein p53; D011005:Plutonium; D000576:Americium