Mode of action of estra-1,3,5(10)-triene-3, 17 beta-diol, 3-benzoate, 17[4-[4-[bis(2-chloroethyl)amino]phenyl]-1-oxobutoxy] acetate] (KM2210) on MCF-7 human breast tumours transplanted into nude mice.

KM2210 is a benzoate of an estradiol-chlorambucil conjugate with three active metabolites, KM2202, estradiol (E2) and chlorambucil (CBL). The mode of action of this compound was assessed using MCF-7 human breast tumours transplanted into nude mice. The growth of MCF-7 in nude mice was inhibited by KM2210 and enhanced by E2, although the serum levels of E2 in nude mice treated with KM2210 and E2 were similar. The antitumour activity of CBL was completely blocked by extrinsic E2, while KM2210 suppressed the growth of MCF-7 in spite of the presence of E2 in the serum of tumour-bearing nude mice. KM2210 and KM2202 suppressed the expression of cytosol estrogen receptor (ER) of MCF-7 cells detected by the dextran-coated charcoal and fluorescent E2 staining method, although CBL did not affect the ER expression of MCF-7 cells. This inhibitory effect of KM2210 on ER was also corroborated by the fact that the pretreatment with KM2210 prevented the E2-stimulated growth of MCF-7 in nude mice. These results indicated that one of the effects induced by KM2210 is the blockage of ER expression in combination with the alkylating antitumour activity of CBL. KM2210 is thought to be a promising agent with unique modes of action for ER-positive breast carcinomas.