The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
The combination of a rexinoid and SERM should be considered for future clinical trials.
Liby
Karen
K
Dartmouth Medical School, Hanover, NH 03755, USA.
Rendi
Mara
M
Suh
Nanjoo
N
Royce
Darlene B
DB
Risingsong
Renee
R
Williams
Charlotte R
CR
Lamph
William
W
Labrie
Fernand
F
Krajewski
Stan
S
Xu
Xiaochun
X
Kim
Heetae
H
Brown
Powel
P
Sporn
Michael B
MB
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009539:Nicotinic Acids / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015996:Survival Rate; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*
D009539:Nicotinic Acids; D010880:Piperidines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C012121:ritetronium; C115121:LY 353381; C095104:LG 100268