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Experimental α-particle radioimmunotherapy of breast cancer using (227)Th-labeled p-benzyl-DOTA-trastuzumab

BACKGROUND: The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate (227)Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. METHODS: Biodistrib...

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Detalles Bibliográficos
Autores principales: Abbas, Nasir, Heyerdahl, Helen, Bruland, Øyvind S, Borrebæk, Jørgen, Nesland, Jahn, Dahle, Jostein
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250964/
https://www.ncbi.nlm.nih.gov/pubmed/22214432
http://dx.doi.org/10.1186/2191-219X-1-18
Descripción
Sumario:BACKGROUND: The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate (227)Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. METHODS: Biodistribution of (227)Th-trastuzumab and (227)Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of (227)Th-trastuzumab, (227)Th-rituximab, cold trastuzumab, and saline. The toxicity of (227)Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens. RESULTS: The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of (227)Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide (223)Ra in bone; the latter already explored in clinical phases I and II trials without serious toxicity. A significant dose-dependent antitumor effect was observed for dosages of 200, 400, and 600 kBq/kg of (227)Th-trastuzumab but no effect of 400 and 600 kBq/kg (227)Th-rituximab (non-tumor binding). No serious delayed bone marrow or normal organ toxicity was observed, but there was a statistical significant reduction in blood cell parameters for the highest-dose group of (227)Th-trastuzumab treatment. CONCLUSION: Internalizing (227)Th-trastuzumab therapy was well tolerated and resulted in a dose-dependent inhibition of breast cancer xenograft growth. These results warrant further preclinical studies aiming at a clinical trial in breast cancer patients with metastases to bone.