Kubota T, Koh J, Yamada Y, Oka S, Enomoto K, Ishibiki K, Abe O, Masui O, Asano K
Department of Surgery, School of Medicine, Keio University, Tokyo.
Jpn J Cancer Res. 1988 Nov;79(11):1224-9. doi: 10.1111/j.1349-7006.1988.tb01548.x.
To elucidate the mode of action of busramustine (KM2210), 17 beta- and alpha-busramustine, estradiol and chlorambucil were used for experimental chemo- and endocrino-therapy against hormone-dependent (T-61) and independent (MX-1) human breast carcinomas serially transplanted into BALB/cA female nude mice. Busramustine was administered po daily for 3 weeks at doses of 12.5-300 mg/kg for the beta-isomer and 25-300 mg/kg for the alpha-isomer. Five to 50 mg of estradiol per kg was administered im once, and 3 to 6 mg of chlorambucil per kg was administered po daily for 3 weeks. All of the compounds were effective against estrogen receptor-positive T-61 with a clear dose-response relationship, while estrogen receptor-negative MX-1 was sensitive to all of the agents except estradiol. Since the alpha-isomer of busramustine was effective against both tumor lines, the mode of action of 17 beta-busramustine may not be related to estrogenic action by estradiol released from the maternal compound. However, 17 beta-busramustine generated the estrogen receptor system of T-61 tumor and resulted in the endometrial hyperplasia of tumor-bearing nude mice, suggesting that this compound also has estrogenic action on transplanted human breast carcinoma and tumor-bearing host mice, besides non-estrogenic antitumor activity on human breast carcinoma xenografts.
为阐明布司他丁（KM2210）的作用方式，使用17β-和α-布司他丁、雌二醇和苯丁酸氮芥对连续移植到BALB/cA雌性裸鼠体内的激素依赖性（T-61）和非依赖性（MX-1）人乳腺癌进行实验性化学和内分泌治疗。布司他丁以每日口服给药3周，β-异构体剂量为12.5 - 300mg/kg，α-异构体剂量为25 - 300mg/kg。每千克体重给予5至50mg雌二醇一次皮下注射，每千克体重给予3至6mg苯丁酸氮芥每日口服给药3周。所有化合物对雌激素受体阳性的T-61均有效，且有明确的剂量反应关系，而雌激素受体阴性的MX-1对除雌二醇外的所有药物均敏感。由于布司他丁的α-异构体对两种肿瘤细胞系均有效，17β-布司他丁的作用方式可能与母体化合物释放的雌二醇的雌激素作用无关。然而，17β-布司他丁可诱导T-61肿瘤的雌激素受体系统，并导致荷瘤裸鼠子宫内膜增生，这表明该化合物除了对人乳腺癌异种移植瘤具有非雌激素抗肿瘤活性外，对移植的人乳腺癌和荷瘤宿主小鼠也具有雌激素作用。
