title: Tasisulam sodium, an antitumor agent that inhibits mitotic progression and induces vascular normalization.
abstract: LY573636-sodium (tasisulam) is a small molecule antitumor agent with a novel mechanism of action currently being investigated in a variety of human cancers. In vitro, tasisulam induced apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Using high content cellular imaging and subpopulation analysis of a wide range of in vitro and in vivo cancer models, tasisulam increased the proportion of cells with 4N DNA content and phospho-histone H3 expression, leading to G(2)-M accumulation and subsequent apoptosis. Tasisulam also blocked VEGF, epidermal growth factor, and fibroblast growth factor-induced endothelial cell cord formation but did not block acute growth factor receptor signaling (unlike sunitinib, which blocks VEGF-driven angiogenesis at the receptor kinase level) or induce apoptosis in primary endothelial cells. Importantly, in vivo phenocopying of in vitro effects were observed in multiple human tumor xenografts. Tasisulam was as effective as sunitinib at inhibiting neovascularization in a Matrigel plug angiogenesis assay in vivo and also caused reversible, non G(2)-M-dependent growth arrest in primary endothelial cells. Tasisulam also induced vascular normalization in vivo. Interestingly, the combination of tasisulam and sunitinib significantly delayed growth of the Caki-1 renal cell carcinoma model, whereas neither agent was active alone. These data show that tasisulam has a unique, dual-faceted mechanism of action involving mitotic catastrophe and antiangiogenesis, a phenotype distinct from conventional chemotherapies and published anticancer agents.
authors: Eli Lilly and Company, Oncology, Lilly Corporate Center, Indianapolis, Indiana, USA.
authors: Timothy
authors: T
authors: Meier
authors: Mark
authors: M
authors: Uhlik
authors: Sudhakar
authors: S
authors: Chintharlapalli
authors: Michele
authors: M
authors: Dowless
authors: Robert
authors: R
authors: Van Horn
authors: Julie
authors: J
authors: Stewart
authors: Wayne
authors: W
authors: Blosser
authors: James
authors: J
authors: Cook
authors: Debra
authors: D
authors: Young
authors: Xiang
authors: X
authors: Ye
authors: Glenn
authors: G
authors: Evans
authors: Kelly
authors: K
authors: Credille
authors: Darryl
authors: D
authors: Ballard
authors: Lysiane
authors: L
authors: Huber
authors: Andrew
authors: A
authors: Capen
authors: Marcio
authors: M
authors: Chedid
authors: Robert
authors: R
authors: Ilaria
authors: Michele C
authors: MC
authors: Smith
authors: Louis
authors: L
authors: Stancato
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; C534068:N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide; D013449:Sulfonamides