Mode of Action of Estra-1,3,5(10)-triene-3,17β-diol 3-Benzoate 17-((4-(4-Bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy)acetate) on Human Breast Carcinoma Xenografts in Nude Mice

To elucidate the mode of action of busramustine (KM2210), 17β- and α-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 β-isomer and 25–300 mg/kg for the α-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 α-isomer of busramustine was effective against both tumor lines, the mode of action of 17β-busramustine may not be related to estrogenic action by estradiol released from the maternal compound. However, 17bT-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.