埼玉医科大学雑誌 第31巻 第1号 (2004年1月) 25-31頁 ◇論文(図表を含む全文)は，PDFファイルとなっています．
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Ligand Binding Specificity of Androgen Receptor Mutants detected in Prostate Cancer
Shigeki Tokonabe (Department of Urology, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
Advanced prostate cancer may often progress as an androgen independent tumor in spite of androgen ablation therapies or medication of antiandrogen drugs. This diverse resistance to the hormonal therapies is thought to be due to the amplified, overexpressed or mutated androgen receptor (AR). Previous studies indicated that the mutated AR loses the specificity to the ligands. However, the functional relationship between mutations of AR and specificity of ligands are poorly understood. In this report, the author shows the dissociation constants (Kd) of mutated ARs to eight ligands including an antiandrogen drug (hydroxyflutamide). Only one amino acid mutation in the ligand-binding pocket, can cause a significant change on the binding affinity. Loss of ligand specificity is observed in the mutated AR such as L701H, H874Y, T877A and T877S, of which mutation is located in 3 or 11 α-helix of the ligand binding domain. Various changes of the affinity are seen among the mutants, which suggest that the mutated ARs could be different mechanisms for tumor growth in prostate cancer cell.
Keywords: androgen receptor, mutation, prostate cancer
J Saitama Med School 2004;31:25-31
(Received Nov 13, 2003)