Treatment of HER2-Expressing Breast Cancer and Ovarian Cancer Cells With Alpha Particle-Emitting {sup 227}Th-Trastuzumab

Journal Article · Tue Feb 01 00:00:00 EST 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.08.038· OSTI ID:21499715

Heyerdahl, Helen; Krogh, Cecilie ^[1]; Borrebaek, Jorgen ^[2]; Larsen, Asmund ^[2]; Dahle, Jostein ^[1]

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1. Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo (Norway)
2. Algeta ASA, Kjelsas, Oslo (Norway)

Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate {sup 227}Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ({sup 227}Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of {sup 227}Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene. Methods and Materials: Clonogenic survival and cell growth rates of breast cancer cells treated with {sup 227}Th-trastuzumab were compared with rates of cells treated with nonbinding {sup 227}Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated. Results: SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml {sup 227}Th-trastuzumab for 1 h at 4{sup o}C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines. Conclusions: Clinically relevant activity concentrations of {sup 227}Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of {sup 227}Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with {sup 227}Th-trastuzumab.

• OSTI ID: 21499715
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 79, Issue 2; Other Information: DOI: 10.1016/j.ijrobp.2010.08.038; PII: S0360-3016(10)03118-4; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ALPHA PARTICLES
ANTINEOPLASTIC DRUGS
APOPTOSIS
GROWTH
MAMMARY GLANDS
MONOCLONAL ANTIBODIES
NEOPLASMS
ONCOGENES
OVARIES
RADIATION DOSES
RADIOACTIVITY
RADIOIMMUNOTHERAPY
RBE
THORIUM 227
TOXICITY
TUMOR CELLS
X RADIATION
ACTINIDE NUCLEI
ALPHA DECAY RADIOISOTOPES
ANIMAL CELLS
ANTIBODIES
BODY
CHARGED PARTICLES
DAYS LIVING RADIOISOTOPES
DISEASES
DOSES
DRUGS
ELECTROMAGNETIC RADIATION
EVEN-ODD NUCLEI
FEMALE GENITALS
GENES
GLANDS
GONADS
HEAVY NUCLEI
IMMUNOTHERAPY
IONIZING RADIATIONS
ISOTOPES
MEDICINE
NUCLEAR MEDICINE
NUCLEI
ORGANS
RADIATIONS
RADIOISOTOPES
RADIOLOGY
RADIOTHERAPY
THERAPY
THORIUM ISOTOPES