2-Methoxyestradiol as a Potential Cytostatic Drug in Gliomas?

Gliomas of astrocytic origin show only a limited chemotherapy response. Chemoresistance is most pronounced in glioblastoma multiforme, the most common and most malignant glioma, with median survival times not much longer than one year. Failure of chemotherapy partly relies on protective mechanisms against the commonly used DNA alkylating agents, but also on the constitutive activation of the pro-survival PI3K-Akt pathway in glioma cells, which inhibits apoptosis. Therefore, new drugs with an alternative mechanism, independent of DNA alkylation, are required. The microtubule targeting drug 2-methoxyestradiol (2-ME) efficiently induces mitotic arrest, apoptosis, but also autophagic cell death in glioma cells in vitro. Moreover, it may be able to inhibit vascularization of the highly vascular gliobastomas, because the drug influences blood vessel sprouting via a HIF-1-dependent mechanism. Although high doses of i.p. injected 2-ME were recently shown to be effective in an orthothopic rat glioma model, clinical phase I/II trials revealed low oral bioavailability. One of the most exciting future perspectives will be the currently ongoing development of improved 2-ME analogs. Compounds, sulphamoylated at positions 3 and 17, combine sufficient toxicity against tumor cells with resistance against metabolic degradation and sufficient plasma levels in experimental animals. They were found to be superior in some animal models of tumor growth and vascularization, following oral application.