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.