Cytotoxicity of alpha -particle-emitting 5-\[211At]astato-2-deoxyuridine in human cancer cells

Abstract

This study was performed to determine the cytotoxicity of alpha -particle-emitting 5-\[211At]astato-2'-deoxyuridine (i.e. \[211At]AUdR) for monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. Cells in exponential growth were exposed to varying activity concentrations of \[211At]AUdR and for comparison \[211At]astatide and the Auger electron-emitting analogue, 5-\[125I]iodo-2-deoxyuridine (i.e. \[125I]IUdR). Cell uptake, DNA binding and clonogenic survival as a function of activity concentration in the medium were determined following 2 and 20-h incubations. None of the survival curves had detectable shoulders, an observation consistent with high-LET effects. The A (initial activity concentration 37 yielding 37% cell survival) were significantly lower for both cell lines following 20-h exposure of \[211At]AUdR than \[211At]astatide. After correcting for effects from non-cellassociated activity in the medium, the specific cytotoxicity of cell-associated and DNA-bound \[211At]AUdR was estimated. In the 20-h incubation experiments, the A for DNA-associated 37 \[211At]AUdR corresponded to about one 211At atom bound per cell for both cell lines. Unlike \[211At]AUdR, there was a biphasic survival response to \[125I]IUdR, consistent with the lower fractional uptake of \[125I]IUdR at higher activity concentrations. These studies suggest that \[211At]AUdR warrants further evaluation as an endoradiotherapeutic agent for the treatment of rapidly proliferating cancers.