Zaccheo T, Giudici D, Lombardi P, di Salle E
R. & D./Oncology, Farmitalia Carlo Erba Research Center, Milano, Italy.
Cancer Chemother Pharmacol. 1989;23(1):47-50. doi: 10.1007/BF00258457.
The antitumor activity of the new irreversible aromatase inhibitor 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304) was studied in rats with 7,12-dimethylbenzanthracene (DMBA)-induced tumors; several endocrine parameters were evaluated in these animals. The compound was given s.c. and p.o. twice daily, 6 days/week, for 4 weeks. The control group showed 13% tumor regression (0% complete remission, CR; 13% partial remission, PR). FCE 24304 given s.c. induced 44% (22 + 22) regressions at the dose of 3 mg/kg per day, 70% (40 + 30) at 10 mg/kg per day, 73% (27 + 46) at 30 mg/kg per day, and 70% (50 + 20) at 100 mg/kg per day. FCE 24304 given orally induced 25% (17 + 8) tumor regressions at 30 mg/kg per day and 50% (17 + 33) at 100 mg/kg per day. Rats were killed 4 h after the last dose and the aromatase activity of ovarian microsomes (OAA) was evaluated. OAA was reduced by 56% after s.c. treatment with 3 mg/kg per day FCE 24304; complete OAA suppression (greater than or equal to 96%) was obtained starting at 10 mg/kg per day s.c. Oral treatment slightly reduced OAA only at a dose of 100 mg/kg per day (36%). Body weight increased in all the groups s.c. treated with FCE 24304 but not in those treated orally. The weights of the pituitary, adrenals, and uterus were reduced in rats treated s.c. with 10 and 30 mg/kg per day; at 100 mg/kg per day, a decrease in ovarian weight was observed while uterus weight was similar to that of controls. Oral FCE 24304 increased ovarian weight at a dose of 30 mg/kg per day but not at 100 mg/kg per day. Serum prolactin (PRL) and luteinizing hormone (LH) levels did not change. In conclusion, FCE 24304 given s.c. proved highly effective against DMBA-induced tumors in rats but had less activity when given orally. Its intrinsic androgenic activity, higher after s.c. than after oral treatment, could contribute to the antitumor effect in the intact (premenopausal) rat model.
在7,12-二甲基苯并蒽（DMBA）诱导的肿瘤大鼠模型中研究了新型不可逆芳香化酶抑制剂6-亚甲基雄甾-1,4-二烯-3,17-二酮（FCE 24304）的抗肿瘤活性；对这些动物的多个内分泌参数进行了评估。该化合物通过皮下注射和口服给药，每日两次，每周6天，共4周。对照组显示13%的肿瘤消退（0%完全缓解，CR；13%部分缓解，PR）。皮下注射FCE 24304，剂量为每天3mg/kg时诱导44%（22 + 22）的消退，每天10mg/kg时为70%（40 + 30），每天30mg/kg时为73%（27 + 46）；每天100mg/kg时为70%（50 + 20）。口服FCE 24304，每天30mg/kg时诱导25%（17 + 8）的肿瘤消退，每天100mg/kg时为50%（17 + 33）。在最后一剂给药4小时后处死大鼠，并评估卵巢微粒体的芳香化酶活性（OAA）。每天皮下注射3mg/kg FCE 24304后，OAA降低了56%；从每天皮下注射10mg/kg开始可实现OAA完全抑制（大于或等于96%）。口服治疗仅在每天100mg/kg剂量时轻微降低OAA（36%）。所有皮下注射FCE 24304治疗的组体重均增加，但口服治疗组体重未增加。每天皮下注射10mg/kg和30mg/kg的大鼠垂体、肾上腺和子宫重量减轻；每天100mg/kg时，观察到卵巢重量下降，而子宫重量与对照组相似。口服FCE 24304，每天30mg/kg时卵巢重量增加，但每天100mg/kg时未增加。血清催乳素（PRL）和促黄体生成素（LH）水平未发生变化。总之，皮下注射FCE 24304对大鼠DMBA诱导的肿瘤非常有效，但口服时活性较低。其内在雄激素活性皮下注射后高于口服给药后，这可能有助于在完整（绝经前）大鼠模型中发挥抗肿瘤作用。
