Demers L M, Lipton A, Harvey H A, Kambic K B, Grossberg H, Brady C, Santen R J
Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey 17033.
J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):687-91. doi: 10.1016/0960-0760(93)90283-3.
The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.
芳香化酶活性的药物抑制作用一直是晚期乳腺癌患者临床试验的重点。抑制芳香化酶活性的咪唑类化合物的最新进展表明，它们可作为绝经后乳腺癌患者雌激素生物合成的有效抑制剂用于临床。在这项I期开放标签剂量范围探索研究中，我们检测了CGS 20267对8例转移性乳腺癌患者血液和尿液中雌二醇、雌酮和硫酸雌酮水平的抑制效力。研究包括评估肾上腺和甲状腺功能，以寻找在有效阻断芳香化酶的剂量水平下是否存在一般羟化酶抑制的证据。患者在12周内按0.1和0.25毫克的剂量递增，每天一次服用CGS 20267。初步数据显示，CGS 20267可显著抑制血浆雌二醇、雌酮和硫酸雌酮，部分患者在首次给药后24小时内即可观察到这种抑制作用。治疗2周内雌激素抑制率超过90%。在12周的治疗过程中，未观察到基线或促肾上腺皮质激素（考的松）刺激的皮质醇和醛固酮水平有任何变化。此外，治疗期间24小时尿钠和钾值也没有明显改变。我们得出结论，CGS 20267是绝经后转移性乳腺癌患者雌激素生物合成的一种强效、特异性抑制剂，可有效将血液和尿液中的雌激素降低到检测不到的水平。
