title: Inhibitory effects of aromatase inhibitor on estrogen receptor-alpha positive ovarian cancer in mice.
abstract: BACKGROUND
  Estrogen causes proliferation of ovarian cancer cells. Although hormone therapy with an anti-estrogen agent is an optional therapy for recurrent epithelial ovarian cancers, both basic and clinical researches are insufficient. We here examine the efficacy of an aromatase inhibitor (AI) for peritonitis carcinomatosa, the late stage of ovarian cancer.
  
  
  METHODS
  Estrogen receptor (ER)α was assayed in four ovarian cancer cell lines by the RT-PCR method. Using ovariectomized nude mice, peritonitis carcinomatosa consisting of OVCAR-3 cells with the strongest ERα expression or DISS cells with weaker ERα expression was prepared. The survival period was compared between the letrozole group (5 mg/kg/day orally; n = 10) and the control group (n = 10). In addition, the degree of angiogenesis and occurrence of apoptosis were compared using tumor tissue from the abdominal cavity. The expression of aromatase and the protein involving in ERα signaling were examined in tumors immunohistochemically.
  
  
  RESULTS
  Survival period in OVCAR-3 tumors was significantly prolonged in the letrozole group, compared with the control group (P < 0.05), whereas that in DISS tumors was not different between the both groups. The microvessel density in tumors and expression of VEGF decreased significantly in the letrozole group compared to the control group. The incidence of apoptosis did not differ significantly between these groups. No adverse event was observed accompanying the administration of letrozole. The expressions of aromatase, ERα and FOXP1 that is associated with ERα signaling were reduced in tumors by letrozole administration.
  
  
  CONCLUSIONS
  Letrozole was effective for ovarian cancers with abundant expression of ERα. Inhibition of angiogenesis and of ascites production appeared to contribute to prolongation of the survival period.
authors.forename: Hachidai
authors.initials: H
authors.lastname: Hirakawa
authors.affiliation: Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8261, Japan. yokoyama@cc.hirosaki-u.ac.jp.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hideki
authors.initials: H
authors.lastname: Mizunuma
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001201:Ascites / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D000077289:Letrozole; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009570:Nitriles / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D010534:Peritoneal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D009570:Nitriles; D012097:Repressor Proteins; D014230:Triazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077289:Letrozole; D001141:Aromatase; C561410:CYP19A1 protein, human