2-methoxyestradiol is an estrogen receptor agonist that supports tumor growth in murine xenograft models of breast cancer.

PURPOSE: 2-Methoxyestradiol (2MEO) is being developed as a novel antitumor agent based on its antiangiogenic activity, tumor cell cytotoxicity, and apparent lack of toxicity. However, pharmacologic concentrations of 2MEO bind to estrogen receptors (ER). We have therefore examined the ER activity of 2MEO. EXPERIMENTAL DESIGN: Estrogenic actions of 2MEO were evaluated by changes in gene expression of the ER-positive (MCF7) breast tumor cell line and, in vivo, estrogenicity was assessed in breast tumor xenograft models and by measuring endocrine responses in uterus and liver. RESULTS: In the ER-positive breast tumor cell line (MCF7), microarray experiments revealed that 269 of 279 changes in gene expression common to 2MEO and estradiol were prevented by the ER antagonist, ICI 182,780. Changes in the expression of selected genes and their sensitivity to inhibition by ICI 182,780 were confirmed by quantitative reverse transcription-PCR measurement. Activation of ER in MCF7 cells by 2MEO was further confirmed by stimulation of an estrogen response element-dependent reporter gene that was blocked by ICI 182,780 (1 micromol/L). Doses of 2MEO (15-150 mg/kg) that had no antitumor efficacy in either nu/nu BALB/c or severe combined immunodeficient mice bearing ER-negative MDA-MB-435 tumors had uterotropic and hepatic estrogen-like actions. In female nu/nu BALB/c mice inoculated with the estrogen-dependent MCF7 tumor cells, 2MEO (50 mg/kg/d) supported tumor growth. CONCLUSIONS: Tumor growth enhancement by 2MEO at doses generating serum levels (100-500 nmol/L) that have estrogenic activity suggests that a conservative approach to the further clinical evaluation of this agent should be adopted and that its evaluation in breast cancer is inappropriate.

Factors controlling airway smooth muscle proliferation in asthma.

Airway smooth muscle proliferation has been the focus of considerable attention, as it is a quantitatively important component of the airway wall remodeling response in asthma and has been suggested as a suitable target for the development of novel anti-asthma agents. Such agents are considered likely to reduce airway hyperresponsiveness and, consequently, airway obstruction, resulting in fewer symptoms and exacerbations. Identifying suitable drug targets has proved an elusive goal, as no dominant molecular mechanism for remodeling has emerged. Moreover, recent findings raise some doubt as to whether smooth muscle proliferation per se is the explanation of the increase in smooth muscle cell number in asthma, with alternative explanations including the proposal that cells migrate either from the interstitial compartment or from a circulating precursor stem cell population. Therefore, drug targeting of migration responses should be considered as an alternative approach to regulating the smooth muscle component of airway wall remodeling.