Alpha-particle emitting atomic generator (actinium-225)-labeled trastuzumab (Herceptin) targeting of breast cancer spheroids: Efficacy versus HER2/neu expression Journal Article

Authors: Ballangrud, A. M.; Yang, W. H.; Palm, S.; Enmon, R.; Borchardt, P. E.; Pellegrini, V.; McDevitt, M. R.; Scheinberg, D. A.; Sgouros, G.
Article Title: Alpha-particle emitting atomic generator (actinium-225)-labeled trastuzumab (Herceptin) targeting of breast cancer spheroids: Efficacy versus HER2/neu expression
Abstract: Purpose: The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the α-particle emitting atomic generator, actinium-225 (225Ac), against breast cancer spheroids with different HER2/neu expression levels. 225Ac has a 10-day half-life and a decay scheme yielding four α-particles. Experimental Design: The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of 225Ac- trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period. Results: The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20-30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30-40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR37. An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After α-particle irradiation a DVR37 of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively. Conclusion: These studies suggest that 225Ac-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.
Keywords: controlled study; protein expression; unclassified drug; human cell; drug efficacy; antineoplastic agents; flow cytometry; breast cancer; microscopy, confocal; epidermal growth factor receptor 2; in vitro study; cell line, tumor; breast neoplasms; time factors; dose-response relationship, radiation; monoclonal antibody; antibodies, monoclonal; tumor cell line; radiosensitivity; receptor, erbb-2; radiation beam; drug half life; trastuzumab; radioimmunotherapy; breast metastasis; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; concentration response; alpha radiation; alpha particles; actinium; actinium 225; humans; human; priority journal; article; trastuzumab 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid ac 225; enzyme multiplied immunoassay technique
Journal Title: Clinical Cancer Research
Volume: 10
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2004-07-01
Start Page: 4489
End Page: 4497
Language: English
DOI: 10.1158/1078-0432.ccr-03-0800
PROVIDER: scopus
PUBMED: 15240541
Notes: Clin. Cancer Res. -- Cited By (since 1996):46 -- Export Date: 16 June 2014 -- CODEN: CCREF -- Source: Scopus
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