Exposure of human osteosarcoma and bone marrow cells to tumour-targeted α-particles and γ-irradiation: analysis of cell survival and microdosimetry

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Abstract
This study was designed to compare the cytotoxic effects of an alpha-emitting radioimmunoconjugate, which binds to osteosarcoma but not to bone marrow cells, with those of external gamma-irradiation. The human osteosarcoma cell line, OHS-s1, and mononuclear cells from bone marrow (BM) harvested from healthy donors, were used for these experiments. Cells in suspension were added to various activity concentrations of the anti-osteosarcoma monoclonal antibody TP-3 radiolabelled with 211At. Following incubation for 1 h, unbound radioactivity was washed off and cell survival was determined from clonogenic assays. Microdosimetry was calculated based on binding and retention kinetics of 211At to the cells, as well as cellular and nuclear diameters. For comparison, cell suspensions were irradiated with a single dose of 60Co gamma-rays. 211At-labelled TP-3 showed heterogeneous binding to OHS-s1 cells, with a considerable variation among experiments. About 78% of the initially bound 211At decayed while associated with the OHS-s1 cells. D0 values estimated by microdosimetry were 0.33 (0.22-0.48, range) Gy and 1.18 (0.89-1.89) Gy for OHS-s1 and BM cells, respectively, whereas D0 values after external beam irradiation were 0.86+/-0.07Gy and 1.71+/-0.22Gy. The relative biological effectiveness (RBE) of 211At-labelled TP-3 at 37% survival was 3.43 for OHS-s1 and 1.55 for BM. High-LET targeted alpha-particle exposure killed osteosarcoma cells more effectively than bone marrow cells, although heterogeneous antigen expression among these tumour cells limited the magnitude of this effect.

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