Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Int J Cancer. 2010 Oct 1;127(7):1718-26. doi: 10.1002/ijc.25167.
Long-term treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. Several antiestrogens developed in last decades have been discontinued from clinical testing because of their undesirable effects on the uterus. To avoid such serious side-effect while increasing the drug's anti-breast cancer potential, new triphenylethylene antiestrogens, 2E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and 2E-3-{4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenyl}acrylic acid (SS1010), were designed as safer alternatives. Unlike TAM, SS1020 does not present significant uterotrophic potential in rats; in contrast, SS1010, a compound removing a 4-OH moiety from SS1020, represented weak uterotrophic activity. The structurally related compounds 4-hydroxytamoxifen, toremifene, ospemifene, raloxifene (RAL) and GW5638 all have uterotrophic activity. In addition, SS1020 and SS1010 exhibit no genotoxic activity to damage hepatic DNA in rats. Therefore, SS1020 was selected as a safer antiestrogen candidate and used for evaluating the antitumor potential in animals. At the human equivalent doses of TAM, SS1020 had antitumor potential much higher than that of TAM, RAL and GW5638 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 SS1020. SS1020, lacking estrogenic and genotoxic actions and having strong antitumor potency superior to that of TAM and RAL, could be a safer alternative for breast cancer therapy and prevention.
长期使用他莫昔芬（TAM）会增加女性患子宫内膜癌的风险。过去几十年开发的几种抗雌激素药物因对子宫的不良影响而被停止临床试验。为了避免这种严重的副作用，同时提高药物的抗乳腺癌潜力，设计了新的三苯乙烯类抗雌激素 2E-3-{4-[(E)-4-氯-1-(4- 羟基苯基）-2-苯基丁-1-烯基]苯基}丙烯酸（SS1020）和 2E-3-{4-[(Z)-4-氯-1,2-二苯基丁-1-烯基]苯基}丙烯酸（SS1010）作为更安全的替代品。与 TAM 不同，SS1020 对大鼠没有明显的促子宫生长作用；相比之下，SS1010 是一种从 SS1020 中去除 4-OH 部分的化合物，表现出较弱的促子宫生长活性。结构相关的化合物 4-羟基他莫昔芬、托瑞米芬、奥昔美芬、雷洛昔芬（RAL）和 GW5638 都具有促子宫生长作用。此外，SS1020 和 SS1010 对大鼠的肝 DNA 没有遗传毒性。因此，SS1020 被选为更安全的抗雌激素候选药物，并用于评估动物的抗肿瘤潜力。在 TAM 的人体等效剂量下，SS1020 对 7,12-二甲基苯并（a）蒽诱导的大鼠乳腺癌的抗肿瘤潜力明显高于 TAM、RAL 和 GW5638。SS1020 还有效抑制人 MCF-7 乳腺癌异种移植瘤在裸鼠中的生长。SS1020 缺乏雌激素和遗传毒性作用，具有比 TAM 和 RAL 更强的抗肿瘤效力，可能成为乳腺癌治疗和预防的更安全替代品。
