title: TZT-1027, an antimicrotubule agent, attacks tumor vasculature and induces tumor cell death.
abstract: TZT-1027, a dolastatin 10 derivative, is an antimicrotubule agent with potent antitumor activity both in vitro and in vivo. In this study, we performed biochemical and histopathological examinations, and evaluated TZT-1027-induced tumoral vascular collapse and tumor cell death in an advanced tumor model, murine colon 26 adenocarcinoma. In addition, we studied the effects of TZT-1027 on cultured human umbilical vein endothelial cells (HUVEC). Tolerable doses of TZT-1027 induced tumor-selective hemorrhage within 1 h. This hemorrhage occurred mainly in the peripheral area of the tumor mass. Measurements of tumoral hemoglobin content and dye permeation revealed that the hemorrhage occurred firstly and tumor blood flow stopped secondarily. The vascular damage was followed by continuous induction of apoptosis of the tumor cells, tumor tissue necrosis, and tumor regression. In cultured HUVEC, TZT-1027 induced marked cell contraction with membrane blebbing in 30 min. These cell changes were completely inhibited by K252a, a broad-spectrum inhibitor of protein kinases. These effects of TZT-1027 on both tumor vasculature and HUVEC were greater than those of vincristine. In conclusion, TZT-1027 quickly attacked the well-developed vascular system of advanced tumors by a putative protein kinase-dependent mechanism, and then blocked tumor blood flow. Therefore, TZT-1027 has both a conventional antitumor activity and a unique anti-tumoral vascular activity, making it a potentially powerful tool for clinical cancer therapy.
authors.affiliation: Safety Research Department, Teikoku Hormone Mfg. Co., Ltd., Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan. otani-m@kw.teikoku-hormone.co.jp.
authors.forename: M
authors.initials: M
authors.lastname: Otani
authors.forename: T
authors.initials: T
authors.lastname: Natsume
authors.forename: J I
authors.initials: JI
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Murakoshi
authors.forename: T
authors.initials: T
authors.lastname: Mikami
authors.forename: T
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010539:Permeability; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006454:Hemoglobins; D009842:Oligopeptides; C105791:soblidotin