TAS-108, a novel oral steroidal antiestrogenic agent, is a pure antagonist on estrogen receptor alpha and a partial agonist on estrogen receptor beta with low uterotrophic effect.
OBJECTIVE
Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 compared with other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant.


METHODS
The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) alpha and beta were compared in the reporter assay systems. Their effects on the uterus were evaluated in ovariectomized rat models. The antitumor activity of TAS-108 given p.o. was evaluated in both dimethylbenzanthracene-induced mammary tumor model and human breast cancer MCF-7 cell line xenografts.


RESULTS
TAS-108 inhibited the transactivation of ERalpha under the presence of 17beta-estradiol (E2) and did not induce the transactivation of ERalpha in the absence of E2, unlike the agonistic activity of tamoxifen. On the other hand, it exhibited the most agonistic activity on ERbeta among the antiestrogenic agents tested. When given p.o. in the ovariectomized rat, TAS-108 showed a much weaker estrogenic effect on utterine weight compared to tamoxifen, or with similar levels of raloxifene, a selective estrogen receptor modulator. Also, TAS-108 strongly inhibited tumor growth in dimethylbenzanthracene-induced mammary carcinomain the rat, the endogenous E2 model, at a dosage of 1 to 3 mg/kg/day. It also inhibited high exogenous E2, inducing tumor growth against MCF-7 xenografts at a dosage of 1 mg/kg/day without any toxic manifestation.


CONCLUSIONS
Taken together, p.o. treatment with TAS-108 has a novel mode of action on ERs and inhibits E2-dependent tumor growth with little uterotrophic effect.
Yamamoto
Yasuji
Y
Hanno Research Center, Taiho Pharmaceutical, Co. Ltd., Saitama, Japan. yas-yamamoto@taiho.co.jp
Shibata
Jiro
J
Yonekura
Kazuhiko
K
Sato
Kouji
K
Hashimoto
Akihiro
A
Aoyagi
Yoshimi
Y
Wierzba
Konstanty
K
Yano
Shingo
S
Asao
Tetsuji
T
Buzdar
Aman U
AU
Terada
Tadafumi
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors*; D005260:Female; D000077267:Fulvestrant; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010053:Ovary / Q000378:metabolism; D011485:Protein Binding; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D015533:Transcriptional Activation; D016896:Treatment Outcome; D014599:Uterus / Q000473:pathology*
D002273:Carcinogens; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; C482068:TS 108; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D008156:Luciferases