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Efforts to Control the Errant Products of a Targeted In vivo Generator

¹ Molecular Pharmacology and Chemistry Program; ² Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and ³ Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: David Scheinberg, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-5010; Fax: 212-717-3068; E-mail: d-scheinberg{at}ski.mskcc.org.

Alpha-particle immunotherapy by targeted -emitters or -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.

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