title: Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y.
abstract: alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients.
authors.affiliation: Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Song
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hobbs
authors.forename: Ravy
authors.initials: R
authors.lastname: Vajravelu
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Caroline
authors.initials: C
authors.lastname: Esaias
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
mesh_terms: D000186:Actinium / Q000737:chemistry / Q000627:therapeutic use; D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001729:Bismuth / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007553:Isotope Labeling; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000186:Actinium; D000911:Antibodies, Monoclonal; D001729:Bismuth; D000922:Immunotoxins; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D015021:Yttrium Radioisotopes