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Cancer Susceptibility and Prevention |
Authors' Affiliations: 1 Dartmouth Medical School, Hanover, New Hampshire; 2 Ligand Pharmaceuticals, Inc., San Diego, California; 3 Laval University Medical Center, Quebec, Canada; 4 The Burnham Institute, La Jolla, California; 5 University of Texas M.D. Anderson Cancer Center; and 6 Baylor College of Medicine, Houston, Texas
Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-6558; Fax: 603-650-1129; E-mail: Michael.Sporn{at}dartmouth.edu.
Purpose: We tested whether a selective estrogen receptor modulator (SERM) and a rexinoid are active for prevention and treatment in the mouse mammary tumor virus-neu mouse model of estrogen receptor–negative breast cancer.
Experimental Design: For prevention, mice were fed a powdered control diet, the SERM arzoxifene (Arz, 20 mg/kg diet), the rexinoid LG100268 (268, 30 mg/kg diet), or the combination for 60 weeks. In a second prevention study, mice were fed Arz (6 mg/kg diet), 268 (30 mg/kg diet), the combination of Arz and 268, the SERM acolbifene (Acol, 3 mg/kg diet), or the combination of Acol and 268 for 52 weeks. For the treatment studies, mice with tumors were fed combinations of a SERM and 268 for 4 weeks.
Results: The rexinoid 268 and the SERMs Arz and Acol, as individual drugs, delayed the development of estrogen receptor–negative tumors. Moreover, the combination of a SERM and 268 was strikingly synergistic, as no tumors developed in any mouse fed the combination of 268 and a SERM. Moreover, this drug combination also induced significant tumor regression when used therapeutically. These drugs did not inhibit transgene expression in vitro or in vivo, and the combination of Arz and 268 inhibited proliferation and induced apoptosis in the tumors.
Conclusion: The combination of a rexinoid and SERM should be considered for future clinical trials.
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