Yasui, L. S., Hughes, A. and DeSombre, E. R. Relative Biological Effectiveness of Accumulated ¹²⁵IdU and ¹²⁵I-Estrogen Decays in Estrogen Receptor-Expressing MCF-7 Human Breast Cancer Cells.

The therapeutic potential for delivering a cytotoxic dose of radiation (using the decay of Auger-electron emitters) to the cell nucleus of cancer cells that express estrogen receptors (ERs) by radiolabeled estrogen was investigated in the ER-expressing human breast cancer cell line, MCF-7. The radiolabeled estrogen/ER complex irradiates the cell nucleus by binding specific DNA sequences called estrogen response elements (EREs). Cell clonogenicity and induction of DNA double-strand breaks (DSBs) by γ radiation or accumulation of ¹²⁵I-iododeoxyuridine (¹²⁵IdU) or E-17α[¹²⁵I]iodovinyl-11βmethoxyestradiol (¹²⁵IVME2) decays were determined. MCF-7 cells were efficiently killed by accumulation of ¹²⁵IdU (D₀ = 30 decays per cell) and ¹²⁵IVME2 decays (D₀ = 28 decays per cell). DNA DSBs were induced by the accumulation of ¹²⁵IdU (approximately 3750 decays per cell required to reduce the mean value of the elution profile to 50%) or ¹²⁵IVME2 decays (approximately 465 decays per cell required to reduce the mean value to 50%). For survival of MCF-7 cells after γ irradiation, the D₀ was 1 Gy, and approximately 65 Gy was required to reduce the mean value to 50% for induction of DSBs. The RBE values for cell killing and induction of DSBs by ¹²⁵IVME2 relative to γ radiation were 4.8 and 18.8, respectively. The RBE values for cell killing and induction of DSBs by ¹²⁵IdU relative to γ radiation were 4.5 and 2.3, respectively. Cell killing in a manner similar to that induced by high-LET radiation and the high RBE for induction of DSBs by ¹²⁵IVME2 in the ER-expressing MCF-7 cells provide a biological rationale for the use of Auger electron-emitting radionuclides covalently bound to estrogen to deliver a cytotoxic dose of radiation to ER-positive cancers.