Tumor-specific antivascular effect of TZT-1027 (Soblidotin) elucidated by magnetic resonance imaging and confocal laser scanning microscopy.
TZT-1027 (soblidotin), an antimicrotubule agent, has previously been evaluated in terms of its antivascular effects. In this study, Evans blue perfusion, magnetic resonance imaging (MRI), and confocal laser scanning microscopy (CLSM) were utilized to further elucidate the antivascular effect of TZT-1027 in female nude mice and rats bearing human breast tumor MX-1, as well as in female Sprague-Dawley rats that developed breast tumors induced by dimethylbenz(a)anthracene (DMBA). Therapeutic doses of TZT-1027 caused nearly complete regression of implanted MX-1 tumors in nude mice and rats as well as DMBA-induced tumors in rats. The perfusion in MX-1 tumor implanted in nude mice was drastically reduced within 30 min after TZT-1027 administration and was completely inhibited after 6 h or more, although not reduced in normal tissue of kidney. The study using MRI demonstrated that rich blood flow within tumors was remarkably reduced 1-3 h after TZT-1027 administration both in nude rats bearing MX-1 tumors and in rats with DMBA-induced tumors. Furthermore, the study with CLSM in nude mice bearing MX-1 tumors revealed a disruption of tumor microvessels at 1 h and a destruction of tumor microvessel network at 3 h after TZT-1027 administration. In contrast, these types of vascular disorders were not observed in heart and kidney. These results suggest that TZT-1027 specifically damages tumor vasculatures, leading to extensive tumor necrosis within tolerable dose range, and confirms earlier observations that TZT-1027 exerts a considerable antivascular effect in addition to an excellent cytotoxic effect.
Natsume
Tsugitaka
T
ASKA Pharmaceutical Co., Ltd, R & D Administration, 1604 Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan. natsume-t@aska-pharma.co.jp
Watanabe
Junichi
J
Ogawa
Kenji
K
Yasumura
Kazuhiko
K
Kobayashi
Motohiro
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008279:Magnetic Resonance Imaging; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009842:Oligopeptides; D015127:9,10-Dimethyl-1,2-benzanthracene; C105791:soblidotin