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 gamma radiation or accumulation of (125)I-iododeoxyuridine ((125)IdU) or E-17alpha[(125)I]iodovinyl-11betamethoxyestradiol ((125)IVME2) decays were determined. MCF-7 cells were efficiently killed by accumulation of (125)IdU (D(0) = 30 decays per cell) and (125)IVME2 decays (D(0) = 28 decays per cell). DNA DSBs were induced by the accumulation of (125)IdU (approximately 3750 decays per cell required to reduce the mean value of the elution profile to 50%) or (125)IVME2 decays (approximately 465 decays per cell required to reduce the mean value to 50%). For survival of MCF-7 cells after gamma irradiation, the D(0) 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 (125)IVME2 relative to gamma radiation were 4.8 and 18.8, respectively. The RBE values for cell killing and induction of DSBs by (125)IdU relative to gamma 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 (125)IVME2 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.
Yasui
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L
Northern Illinois University, Department of Biological Sciences, DeKalb, Illinois 60115, USA.
Hughes
A
A
DeSombre
E
E
D000230:Adenocarcinoma / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004583:Electrons; D004705:Endocytosis; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D005720:Gamma Rays; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000528:radiation effects; D021381:Protein Transport; D011960:Receptors, Estrogen / Q000378:metabolism*; D012062:Relative Biological Effectiveness; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D004958:Estradiol; C042716:17 alpha-iodovinyl-11 beta-methoxyestradiol; D007065:Idoxuridine