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Apoptosis Induction and Potent Antiestrogen Receptor-negative Breast Cancer Activity in Vivo by a Retinoid Antagonist¹

MAXIA Pharmaceuticals, Inc. [A. N. F., H. A-S., M. P.], and Sidney Kimmel Cancer Center [A. N. F., F. J. P., M. P.], San Diego, California 92121

Close to 180,000 women will be diagnosed with breast cancer this year in the United States and more than 43,000 will die from this disease. Antiestrogens have shown promise, but they can only be effective against estrogen-dependent stages of the disease. We identify here a retinoid antagonist, MX781, that is effective against estrogen receptor-positive and -negative breast cancer cells. Although classical retinoids show limited efficacy and significant side effects, this novel compound kills breast cancer cells by inducing apoptosis and is effective against estrogen receptor-negative human breast cancer tumors in vivo. Remarkably, MX781 is well tolerated and does not seem to have significant toxicity. This novel retinoid antagonist, therefore, represents a promising new candidate for the treatment of breast cancer.

¹ This work was supported in part by a grant from the Breast Cancer Research Program of the University of California (2CB-01101) and NCl Grant CA55681.

² To whom requests for reprints should be addressed, at MAXIA Pharmaceuticals, Inc., 10835 Altman Row, Suite 250, San Diego, CA 92121. Phone: (619) 824-1779; Fax: (619) 824-1967.

Received 6/ 4/98. Accepted 8/27/98.

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