Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo.
TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.
Natsume
Tsugitaka
T
Medicinal Research Department, Teikoku Hormone Mfg. Co., Ltd., Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan.
Watanabe
Jun-ichi
J
Koh
Yasuhiro
Y
Fujio
Nami
N
Ohe
Yuichiro
Y
Horiuchi
Toshi
T
Saijo
Nagahiro
N
Nishio
Kazuto
K
Kobayashi
Motohiro
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000627:therapeutic use*; D012867:Skin / Q000473:pathology; D013267:Stilbenes / Q000627:therapeutic use; D043823:Taxoids / Q000627:therapeutic use; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014750:Vincristine / Q000627:therapeutic use
D000970:Antineoplastic Agents; D009842:Oligopeptides; D013267:Stilbenes; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D014750:Vincristine; C105791:soblidotin; C058728:fosbretabulin