Antivascular effects of TZT-1027 (Soblidotin) on murine Colon26 adenocarcinoma.
We investigated the ability of TZT-1027 (Soblidotin), a novel antimicrotubule agent, to induce antivascular effects, because most vascular targeting agents that selectively disrupt tumor vasculature also inhibit tubulin polymerization. Treatment with 10(-7) g/mL TZT-1027 rapidly disrupted the microtubule cytoskeleton in human umbilical vascular endothelial cells (HUVEC), and significantly enhanced vascular permeability in HUVEC monolayers. In addition, single intravenous administration of 2 mg/kg TZT-1027 to mice bearing Colon26 tumors significantly reduced tumor perfusion and caused extravascular leakage of erythrocytes 1 h after administration. Subsequently, thrombus formation with deposition of fibrin and tumor necrosis was observed 3 and 24 h after administration, respectively. These results strongly suggest that TZT-1027 possesses antivascular effects. TZT-1027 induced apoptosis not only in HUVEC but also in C26 cancer cells (cell line of Colon26 solid tumor) in vitro, suggesting it exerts direct cytotoxicity against tumor cells in addition to its antivascular effects. A single intravenous administration of 1, 2 and 4 mg/kg TZT-1027 significantly prolonged the survival of mice with advanced-stage Colon26 tumors in a dose-dependent manner. Furthermore, TZT-1027 itself less markedly enhanced the permeability of normal vessels, but was additive with vascular endothelial growth factor, indicating the possibility that TZT-1027 selectively exerts its activity on tumor vessels. In summary, these results suggest that TZT-1027 exerts both an indirect antivascular effect and a direct cytotoxic effect, resulting in strong antitumor activity against advanced-stage tumors, and that TZT-1027 may be useful clinically for treating solid tumors.
Watanabe
Junichi
J
ASKA Pharmaceutical Co., Ltd., Research & Development Division, 1604 Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan. watanabe-j@aska-pharma.co.jp
Natsume
Tsugitaka
T
Kobayashi
Motohiro
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D012867:Skin / Q000166:cytology / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; D009842:Oligopeptides; C105791:soblidotin