MODE OF ACTION OF ESTRA-1,3,5(10)-TRIENE-3, 17-BETA-DIOL, 3-BENZOATE,4-[4-[BIS(2-CHLOROETHYL)AMINO]PHENYL]-1-OXOBUTOXY] ACETATE] (KM2210) ON MCF-7 HUMAN BREAST-TUMORS TRANSPLANTED INTO NUDE-MICE

KM2210 is a benzoate of an estradiol-chlorambucil conjugate with three active metabolites, KM2202, estradiol (E2) and chlorambucil (CBL). Th e mode of action of this compound was assessed using MCF-7 human breas t tumours transplanted into nude mice. The growth of MCF- 7 in nude mi ce was inhibited hy KM2210 and enhanced by EZ although the serum level s of E2 in nude mice treated with KM2210 and E2 were similar. The anti tumour activity of CBL was completely blocked by extrinsic E2, while K M2210 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 t he expression of cytosol estrogen receptor (ER) of MCF-7 cells detecte d by the dextran-coated charcoal and fluorescent E2 staining method, a lthough CBL did not affect the ER expression of MCF- 7 cells. This inh ibitory 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 induc ed by KM2210 is the blockage of ER expression in combination with the alkylating antitumour activity of CBL. KM2210 is thought to be a promi sing agent with unique modes of action for ER-positive breast carcinom as.