In the present study, rather convincing evidence for an alternative mechanism of antiestrogen action through a non-receptor-mediated pathway is provided. Antiestrogens are shown to alter cytotoxicity of melphalan and fluorouracil without themselves exerting growth inhibitory effects. While the mechanism(s) of this remain to be determined, these studies should provide several important caveats to clinical investigators. First, empirical drug combinations should not be assumed to increase activity. Whenever possible scheduling and drug combinations should be rationally explored in vitro and in animal models. Second, other molecular sites of action aside from the high-affinity estrogen receptor must clearly exist for antiestrogens and their role as targets for therapeutic intervention need to be explored. Whether these will turn out to be the ubiquitous but undefined antiestrogen binding sites previously described will await further study.
ASJC Scopus subject areas
- Cancer Research