TREATMENT OF HER2-EXPRESSING BREAST CANCER AND OVARIAN CANCER CELLS WITH ALPHA PARTICLE-EMITTING 227TH-TRASTUZUMAB

Purpose: To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate Th-227-p-isothiocyanato-benzyl-DOTA-trastuzumab (Th-227-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 Th-227-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 Th-227-trastuzumab were compared with rates of cells treated with nonbinding Th-227-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/m1 Th-227-trastuzumab for 1 h at 4 degrees 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 Th-227-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of Th-227-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 Th-227-trastuzumab. (C) 2011 Elsevier Inc.