Antitumor activity of TZT‐1027 (Soblidotin) against vascular endothelial growth factor‐secreting human lung cancer in vivo

Abstract

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.