Schieweck K, Bhatnagar A S, Batzl C, Lang M
Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):633-6. doi: 10.1016/0960-0760(93)90270-7.
The non-steroidal aromatase inhibitor CGS 20,267, at maximally effective doses in non-tumor bearing adult female rats, elicits endocrine effects mimicking those seen after surgical ovariectomy and thus induces a "medical" ovariectomy. We now report on studies characterizing the anti-tumor and endocrine effects of three orally active non-steroidal aromatase inhibitors, CGS 20,267, CGP 45,688 and CGP 47,645, in adult female rats bearing estrogen-dependent DMBA-induced mammary tumors. Doses ranging from 3 to 3000 micrograms/kg were given by gavage once daily for 6 weeks. After 6 weeks of treatment, the ED50 for suppression of tumor volume was 10-30, 100 and 3-10 micrograms/kg for CGS 20,267, CGP 45,688 and CGP 47,645, respectively. The maximally effective dose for anti-tumor efficacy was 300, 1000 and 100 micrograms/kg for each of the three inhibitors, respectively. The observed potent anti-tumor efficacy was accompanied by potent endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats remained in constant diestrus) was observed in all animals from the 2nd or 3rd week of treatment to the end of the 6-week treatment period. Uterine weight, at the maximally effective doses for each of the three inhibitors, was suppressed to between 42 and 28% of pre-treatment levels. This suppression was similar to the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy. Serum estradiol concentrations in rats treated with 300 micrograms/kg CGS 20,267 were significantly suppressed to 12% of pre-treatment levels and serum luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the three non-steroidal aromatase inhibitors was accompanied in each case by a variety of endocrine effects corresponding to those seen after ovariectomy.
非甾体类芳香化酶抑制剂CGS 20,267，在未患肿瘤的成年雌性大鼠中使用最大有效剂量时，会引发类似于手术去卵巢后所见的内分泌效应，从而诱导“药物性”去卵巢。我们现在报告关于三种口服活性非甾体类芳香化酶抑制剂CGS 20,267、CGP 45,688和CGP 47,645在患有雌激素依赖性二甲基苯并蒽（DMBA）诱导的乳腺肿瘤的成年雌性大鼠中的抗肿瘤和内分泌效应的研究。剂量范围为3至3000微克/千克，通过灌胃每天给药一次，持续6周。治疗6周后，CGS 20,267、CGP 45,688和CGP 47,645抑制肿瘤体积的半数有效剂量（ED50）分别为10 - 30、100和3 - 10微克/千克。三种抑制剂各自的抗肿瘤功效最大有效剂量分别为300、1000和100微克/千克。观察到的强效抗肿瘤功效伴随着强效内分泌效应。因此，在从治疗的第2周或第3周直至6周治疗期结束的所有动物中，均观察到卵巢周期性的破坏（在最大剂量下大鼠处于持续的动情间期）。在三种抑制剂各自的最大有效剂量下，子宫重量被抑制至治疗前水平的42%至28%之间。这种抑制类似于去卵巢后所见的子宫重量抑制（治疗前的27%）。用300微克/千克CGS 20,267治疗的大鼠血清雌二醇浓度显著抑制至治疗前水平的12%，血清促黄体生成素（LH）浓度比治疗前水平升高3至4倍。因此，三种非甾体类芳香化酶抑制剂各自所见的强效抗肿瘤功效在每种情况下都伴随着与去卵巢后所见相对应的多种内分泌效应。
