title: Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models.
abstract: Antitumor activities of YM155, a novel small-molecule survivin suppressant, were investigated in a wide variety of human cancer cell lines and xenograft models. YM155 inhibited the growth of 119 human cancer cell lines, with the greatest activity in lines derived from non-Hodgkin's lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia and melanoma. The mean log growth inhibition of 50% (GI(50) ) value was 15 nM. The mean GI(50) values of YM155 were 11 nM for p53 mut/null cell lines and 16 nM for p53 WT cell lines, suggesting that YM155 inhibits the growth of human tumor cell lines regardless of their p53 status. In non-small-cell lung cancer (Calu 6, NCI-H358), melanoma (A375), breast cancer (MDA-MB-231) and bladder cancer (UM-UC-3) xenograft models, 3- or 7-day continuous infusions of YM155 (1-10 mg/kg) demonstrated significant antitumor activity without showing significant bodyweight loss. Tumor regressions induced by YM155 were associated with reduced intratumoral survivin expression levels, increased apoptosis and decreased mitotic indices. The broad and potent antitumor activity presented in the present study is indicative of the therapeutic potential of YM155 in the clinical setting.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan. takahito.nakahara@jp.astellas.com
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakahara
authors.forename: Aya
authors.initials: A
authors.lastname: Kita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mori
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Amino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tominaga
authors.forename: Isao
authors.initials: I
authors.lastname: Kinoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudou
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009285:Naphthoquinones / Q000494:pharmacology*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium