Cytotoxicity of estramustine, a steroid-nitrogen mustard derivative, through non-DNA targets.

Estramustine is cytotoxic in HeLa and Walker 256 carcinoma cells (with or without acquired resistance to nitrogen mustards) at concentrations equivalent to other alkylating agents. Even at lethal estramustine levels, no damage to DNA occurs. Instead, a disproportionately high amount of intact estramustine binds hydrophobically to the structural proteins of the nucleus, the nuclear matrix. In HeLa cells, estradiol receptors are absent, and estradiol per se is not toxic. Thus, estramustine has a mechanism of action distinct from that of steroids and alkylating agents and may induce cytotoxicity through interactions with the proteins of the nuclear matrix.