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Promising Preclinical Activity of 2-Methoxyestradiol in Multiple Myeloma¹

Molecular Medicine Program [D. D., S. J. R.] and Division of Hematology [M. T., T. E. W., S. V. R.], Mayo Clinic and Foundation, Rochester, Minnesota 55905

Purpose: 2-Methoxyestradiol (2ME2), a natural endogenous product of estradiol metabolism, has demonstrated activity against tumor cell lines and can inhibit angiogenesis. There are limited treatment options for patients with multiple myeloma (MM) who relapse after high-dose therapy and stem cell transplantation. We studied the preclinical activity of 2ME2 as a therapeutic agent for myeloma.

Experimental Design: Five established myeloma cell lines as well as primary plasma cells from patients with MM were exposed to 2ME2 at various concentrations. We evaluated the activity of the drug to inhibit cell replication and induction of apoptosis in vitro as well as the ability of the drug to inhibit myeloma tumor xenograft growth in severe combined immunodeficient mice.

Results: 2ME2 inhibited tritiated thymidine uptake in all myeloma cell lines tested in a dose-dependent fashion and induced G₂-M phase cell cycle arrest. The drug induced apoptosis in all cell lines tested and in half of the primary plasma cells evaluated in a dose-response manner. Forty-eight h after drug exposure, a large proportion of the cells were dead by propidium iodide staining. Injection of the drug i.p. suppressed myeloma tumor xenograft growth, and the effect was sustained after cessation of therapy.

Conclusions: 2ME2 has significant activity against myeloma cell lines and primary myeloma cells both in vitro and in an animal model. Clinical trials are required to evaluate its activity in patients with MM.

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