title: Efforts to control the errant products of a targeted in vivo generator.
abstract: Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P < 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P < 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P < 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Jaspreet Singh
authors.initials: JS
authors.lastname: Jaggi
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Kappel
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Flombaum
authors.forename: Catalina
authors.initials: C
authors.lastname: Cabassa
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000186:Actinium / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001729:Bismuth / Q000737:chemistry / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000494:pharmacology*; D005260:Female; D005605:Francium / Q000737:chemistry / Q000493:pharmacokinetics; D000922:Immunotoxins / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D016499:Radioimmunotherapy / Q000379:methods*; D004113:Succimer / Q000494:pharmacology; D014494:Unithiol / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D000922:Immunotoxins; D005605:Francium; D014494:Unithiol; D004113:Succimer; D000186:Actinium; D001729:Bismuth