Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
Int J Cancer. 2011 Feb 15;128(4):974-82. doi: 10.1002/ijc.25659. Epub 2010 Oct 29.
Treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. The carcinogenic effect is thought to involve initiation and/or promotion resulting from DNA damage induced by TAM as well as its estrogenic action. To minimize this serious side-effect while increasing the anti-breast cancer potential, a new benzopyran antiestrogen, 2E-3-{4-[(7-hydroxy-2-oxo-3-phenyl-2H-chromen-4-yl)-methyl]-phenyl}-acrylic acid (SS5020), was synthesized. Unlike TAM, SS5020 exhibits no genotoxic activity to damage DNA. Furthermore, SS5020 does not present significant uterotrophic potential in rats; in contrast, the structurally related compounds, TAM, toremifene, raloxifene (RAL) and SP500263 all have uterotrophic activity. At the human equivalent molar dose of TAM (0.33 or 1.0 mg/kg), SS5020 had much stronger antitumor potential than those same antiestrogens against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS5020. SS5020, lacking genotoxic and estrogenic actions, could be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer therapy and prevention.
他莫昔芬（TAM）治疗会增加女性患子宫内膜癌的风险。致癌作用被认为涉及 TAM 诱导的 DNA 损伤的启动和/或促进，以及其雌激素作用。为了在增加抗乳腺癌潜力的同时最小化这种严重的副作用，合成了一种新的苯并吡喃类抗雌激素，2E-3-{4-[(7-羟基-2-氧代-3-苯基-2H-色烯-4-基）-甲基]-苯基}-丙烯酸（SS5020）。与 TAM 不同，SS5020 没有表现出导致 DNA 损伤的遗传毒性活性。此外，SS5020 对大鼠没有明显的促子宫作用；相比之下，结构相关的化合物，他莫昔芬、托瑞米芬、雷洛昔芬（RAL）和 SP500263 都具有促子宫作用。在与 TAM 相同的人等效摩尔剂量（0.33 或 1.0mg/kg）下，SS5020 对 7,12-二甲基苯并（a）蒽诱导的大鼠乳腺癌的抗肿瘤潜力比这些相同的抗雌激素强得多。SS5020 也有效抑制了植入裸鼠的人 MCF-7 乳腺癌异种移植物的生长。缺乏遗传毒性和雌激素作用的 SS5020 可能是治疗和预防乳腺癌的更安全、更强的 TAM 和 RAL 替代抗雌激素。
